Smarca degraders and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.17/132,764, filed Dec. 23, 2020, which claims the benefit of U.S.Provisional Appl. No. 62/952,578, filed Dec. 23, 2019 and U.S.Provisional Appl. No. 63/123,176, filed Dec. 9, 2020, the contents ofeach of which are herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for themodulation of one or more SWI/SNF-related matrix-associatedactin-dependent regulator of chromatin subfamily A (“SMARCA”) and/orpolybromo-1 (“PB1”) protein via ubiquitination and/or degradation bycompounds according to the description provided herein. The disclosurealso provides pharmaceutically acceptable compositions comprisingcompounds of the present description and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades m isfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See e.g., Li et al. “Genome-wide and functionalannotation of human E3 ubiquitin ligases identifies MULAN, amitochondrial E3 that regulates the organelle's dynamics and signaling.”PLOS One 2008, (3)1487; Berndsen et al. “New insights into ubiquitin E3ligase mechanism” Nat. Struct. Mol. Biol. 2014, 21:301; Deshaies et al.“RING domain E3 ubiquitin ligases” Ann. Rev. Biochem. 2009, 78:399;Spratt et al. “RBR E3 ubiquitin ligases: new structures, new insights,new questions” Biochem. 2014, 458:421; and Wang et al. “Roles of F-boxproteins in cancer” Nat. Rev. Cancer 2014, 14:233.

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

The UPP is used to induce selective protein degradation, including useof fusion proteins to artificially ubiquitinate target proteins andsynthetic small-molecule probes to induce proteasome-dependentdegradation. Bifunctional compounds composed of a target protein-bindingligand and an E3 ubiquitin ligase ligand, induced proteasome-mediateddegradation of selected proteins via their recruitment to E3 ubiquitinligase and subsequent ubiquitination. These drug-like molecules offerthe possibility of temporal control over protein expression. Suchcompounds are capable of inducing the inactivation of a protein ofinterest upon addition to cells or administration to an animal or human,and could be useful as biochemical reagents and lead to a new paradigmfor the treatment of diseases by removing pathogenic or oncogenicproteins. See e.g., Crews, Chem. & Biol. 2010, 17(6):551; Schneeklothand Crews, ChemBioChem 2005, 6(1):40.

An ongoing need exists in the art for effective treatments for disease,especially hyperplasia and cancers. However, non-specific effects, andthe inability to target and modulate certain classes of proteinsaltogether, such as transcription factors, remain as obstacles to thedevelopment of effective anti-cancer agents. As such, small moleculetherapeutic agents that leverage UPP mediated protein degradation totarget cancer-associated proteins such as one or more SWI/SNF-relatedmatrix-associated actin-dependent regulator of chromatin subfamily A(“SMARCA”) and/or polybromo-1 (“PB1”) protein hold prom ise astherapeutic agents. Accordingly, there remains a need to find compoundsthat are SMARCA degraders useful as therapeutic agents.

SUMMARY OF THE INVENTION

The present disclosure relates to novel compounds, which function torecruit one or more SMARCA2, SMARCA4, or PB1 protein to E3 ubiquitinligases for degradation or directly facilitate ubiquitination fordegradation, and methods of preparation and uses thereof. In particular,the present disclosure provides bifunctional compounds, which findutility as modulators of targeted ubiquitination of SMARCA and/or PB1proteins, which are then degraded and/or otherwise inhibited by thebifunctional compounds as described herein. Also provided are monovalentcompounds, which find utility as inducers of targeted ubiquitination ofSMARCA and/or PB1 proteins, which are then degraded and/or otherwiseinhibited by the monovalent compounds as described herein. An advantageof the compounds provided herein is that a broad range ofpharmacological activities is possible, consistent with thedegradation/inhibition of SMARCA and/or PB1 proteins. In addition, thedescription provides methods of using an amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, e.g., lung cancer.

The present application further relates to targeted degradation ofSMARCA and/or PB1 proteins through the use of bifunctional molecules,including bifunctional molecules that link a cereblon-binding moiety toa ligand that binds SMARCA and/or PB1 proteins.

It has now been found that compounds of this disclosure, andpharmaceutically acceptable compositions thereof, are effective asdegraders of SMARCA and/or PB1 proteins. Such compounds have the generalformula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present disclosure, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating SMARCA and/or PB1 proteins. Such diseases,disorders, or conditions include those described herein.

Compounds provided by this disclosure are also useful for the study ofSMARCA and/or PB1 proteins in biological and pathological phenomena; thestudy of intracellular signal transduction pathways occurring in bodilytissues; and the comparative evaluation of new SMARCA and/or PB1inhibitors or SMARCA and/or PB1 degraders or other regulators of cellcycling, metastasis, angiogenesis, and immune cell evasion, in vitro orin vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present disclosure, and compositions thereof, areuseful as degraders and/or inhibitors of SMARCA and/or PB1 proteins. Insome embodiments, a provided compound degrades and/or inhibits one ormore of SMARCA2, SMARCA4, and PB1 protein.

In certain embodiments, the present invention provides a compound offormula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   SMARCA is a protein binding moiety capable of binding to one or        more of SMARCA2, SMARCA4, and PB1;    -   L is a bivalent moiety that connects SMARCA to DIM; and    -   DIM is a degradation inducing moiety selected from an E3        ubiquitin ligase binding moiety (LBM), lysine mimetic, or        hydrogen atom.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chem istry and Physics,111 Ed. Additionally, general principles of organic chem istry aredescribed in “Organic Chem istry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chem istry”,5^(th) Ea Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York:2001, the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C3-C6 hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNW′ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ±NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted” means that oneor more hydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R∘ may be substituted as definedbelow and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR¹),—(CH₂)₀₋₂0H, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•)3, —OSiR^(•)3, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*2)₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R¹ is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R¹ isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(•)include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•)isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted—OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R¹, -(haloR¹), —OH, —OR¹, —O(haloR¹), —CN, —C(O)OH, —C(O)OR¹,—NH₂, —NHR¹, —NR¹ ₂, or —NO₂, wherein each R¹ is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and isindependently C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, pamoate, pectinate, persulfate,3-phenylpropionate, phosphate, pivalate, propionate, stearate,succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate,undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

As used herein, the term “and/or” is used in this disclosure to meaneither “and” or “or” unless indicated otherwise.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits a SMARCA and/or PB1protein with measurable affinity.In certain embodiments, an inhibitor has an IC₅₀ and/or binding constantof less than about 50 μM, less than about 1 μM, less than about 500 nM,less than about 100 nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term “degrader” is defined as a monovalent orbifunctional compound that binds to and/or inhibits a SMARCA and/or PB1protein and optionally an E3 ligase with measurable affinity resultingin the ubiqitination and subsequent degradation of the SMARCA and/or PB1protein. In certain embodiments, a degrader has an DC₅₀ of less thanabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, less than about 10 nM, or less than about 1 nM. As usedherein, the term “monovalent” refers to a compound without an appendedE3 ligase.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chem istry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chem istryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in a SMARCA and/or PB1 proteinactivity between a sample comprising a compound of the presentinvention, or composition thereof, and a SMARCA and/or PB1 protein, andan equivalent sample comprising a SMARCA and/or PB1 protein, in theabsence of said compound, or composition thereof.

3. DESCRIPTION OF EXEMPLARY EMBODIMENTS

As described above, in certain embodiments, the present disclosureprovides a compound of formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   SMARCA is a protein binding moiety capable of binding to one or        more of SMARCA2, SMARCA4, and PB1;    -   L is a bivalent moiety that connects SMARCA to DIM; and    -   DIM is a degradation inducing moiety selected from an E3        ubiquitin ligase binding moiety (LBM), lysine mimetic, or        hydrogen atom.

SMARCA Binding Moiety (SMARCA)

As defined above and described herein, SMARCA is a SMARCA binding moietycapable of binding to one or more of SMARCA2, SMARCA4, and PB1. In someembodiments, SMARCA is a SMARCA binding moiety capable of degrading oneor more of SMARCA2, SMARCA4, and PB1.

In some embodiments SMARCA is a binding moiety capable of selectivelybinding and degrading SMARCA2 over SMARCA4 and/or PB1. In someembodiments, SMARCA is a binding moiety capable of selectively bindingand degrading SMARCA4 over SMARCA2 and/or PB1. In some embodiments,SMARCA is a binding moiety capable of selectively binding and degradingPB1 over SMARCA2 and/or SMARCA4. In some embodiments, SMARCA is abinding moiety capable of selectively binding and degrading SMARCA2 andSMARCA4 over PB1. In some embodiments, SMARCA is a binding moietycapable of selectively binding and degrading SMARCA2 and PB1 overSMARCA4. In some embodiments, SMARCA is a binding moiety capable ofselectively binding and degrading SMARCA4 and PB1 over SMARCA2. In someembodiments, SMARCA is a binding moiety capable of binding and degradingSMARCA2, SMARCA4, and PB1.

In certain embodiments, the present invention provides a compound offormula I-a:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and DIM        are as defined above and described herein, and wherein:    -   each of Ring V, Ring W, and Ring Y is independently a fused,        spiro-fused, or both fused and spiro-fused ring selected from        6-membered aryl, 5 to 6-membered heteroaryl containing 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 4 to 9-membered saturated or partially unsaturated        monocyclic, bicyclic, or bridged bicyclic carbocyclyl or        heterocyclyl with 1-4 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, and sulfur, wherein each of        Ring V, Ring W, and Ring Y is independently and optionally        further substituted with 1-2 oxo groups;    -   R^(w) is selected from

or hydrogen;

-   -   Ring Z is phenyl, a 5-7 membered saturated or partially        unsaturated carbocyclic or heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur,        wherein Ring Z is further optionally substituted with 1-2 oxo        groups;    -   each of R^(x) and R^(y) is independently hydrogen, deuterium,        R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R,        —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,        —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,        —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,        —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,        —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; or two R groups or two R^(y)        groups are optionally taken together to form an optionally        substituted 5-7 membered partially unsaturated or aryl fused        ring having 0-2 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same atom are taken together with their            intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the atom to which they are            attached, independently selected from nitrogen, oxygen, and            sulfur;    -   each R^(z) is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L^(x) is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—,        —S—, —S(O)₂— or —CR═CR—; and    -   x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16; and    -   y is 0, 1, 2, 4, or 5.

In certain embodiments, the present invention provides a compound offormula I-b:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and DIM        are as defined above and described herein, and wherein:    -   each of Ring V, Ring W, Ring X, and Ring Y is independently a        fused, spiro-fused, or both fused and spiro-fused ring selected        from 6-membered aryl, 5 to 6-membered heteroaryl containing 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 4 to 9-membered saturated or partially unsaturated        monocyclic, bicyclic, or bridged bicyclic carbocyclyl or        heterocyclyl with 1-4 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, and sulfur, wherein each of        Ring V, Ring W, Ring X, and Ring Y is independently and        optionally further substituted with 1-2 oxo groups;

-   -   R^(w) is selected from or hydrogen;    -   Ring Z is phenyl, a 5-7 membered saturated or partially        unsaturated carbocyclic or heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur,        wherein Ring Z is further optionally substituted with 1-2 oxo        groups;    -   each of R^(x) and R^(y) is independently hydrogen, deuterium,        R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R,        —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,        —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,        —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,        —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,        —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; or        -   two R^(x) groups or two R^(y) groups are optionally taken            together to form an optionally substituted 5-7 membered            partially unsaturated or aryl fused ring having 0-2            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same atom are taken together with their            intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the atom to which they are            attached, independently selected from nitrogen, oxygen, and            sulfur;    -   each R^(z) is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L^(x) is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—,        —S—, —S(O)₂— or —CR═CR—; and    -   x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16; and    -   y is 0, 1, 2, 4, or 5.

In certain embodiments, the present invention provides a compound offormula I-c or I-d:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of Ring V and Ring Y is independently an optionally fused        or spiro-fused ring selected from 6-membered aryl, 5 to        6-membered heteroaryl containing 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur, and a 4 to        9-membered saturated or partially unsaturated monocyclic,        bicyclic, or bridged bicyclic carbocyclyl or heterocyclyl with        1-4 heteroatoms independently selected from boron, nitrogen,        oxygen, silicon, and sulfur, wherein each of Ring V and Ring Y        is independently and optionally further substituted with 1-2 oxo        groups;

-   -   R^(w) is selected from or hydrogen;    -   Ring Z is phenyl, a 5-7 membered saturated or partially        unsaturated carbocyclic or heterocyclic ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur,        wherein Ring Z is further optionally substituted with 1-2 oxo        groups;    -   each of R^(x) and R^(y) is independently hydrogen, deuterium,        R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R,        —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,        —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,        —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,        —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,        —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; or        -   two R^(x) groups or two R^(y) groups are optionally taken            together to form an optionally substituted 5-7 membered            partially unsaturated or aryl fused ring having 0-2            heteroatoms independently selected from nitrogen, oxygen, or            sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same atom are taken together with their            intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the atom to which they are            attached, independently selected from nitrogen, oxygen, and            sulfur;    -   each R^(z) is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L^(x) is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—,        —S—, —S(O)₂— or —CR═CR—; and    -   n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16; and    -   m is 0, 1, 2, 4, or 5.

As described herein, a core structure depicted as

includes for example, structures

As defined herein and described above, wherein a formula is depictedusing square brackets, e.g,

L is attached to a modifiable carbon, oxygen, or nitrogen atom withinSMARCA including substitution or replacement of a defined group inSMARCA.

As defined above and described herein, in some embodiments, each of RingV, Ring W, Ring X, and Ring Y is independently a fused, spiro-fused, orboth fused and spiro-fused ring selected from 6-membered aryl, 5 to6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and a 4 to 9-membered saturated orpartially unsaturated monocyclic, bicyclic, or bridged bicycliccarbocyclyl or heterocyclyl with 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, wherein each of RingV, Ring W, Ring X, and Ring Y is independently and optionally furthersubstituted with 1-2 oxo groups.

In some embodiments, one or more of Ring V, Ring W, Ring X, and Ring Yis an optionally fused 6-membered aryl. In some embodiments, one or moreof Ring V, Ring W, Ring X, and Ring Y is an optionally fused 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, one or more of RingV, Ring W, Ring X, and Ring Y is an optionally fused and/or spiro-fused4 to 9-membered saturated or partially unsaturated monocyclic, bicyclic,or bridged bicyclic carbocyclyl. In some embodiments, one or more ofRing V, Ring W, Ring X, and Ring Y is an optionally fused and/orspiro-fused 4 to 9-membered saturated or partially unsaturatedmonocyclic, bicyclic, or bridged bicyclic heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur. In some embodiments, one or more of Ring V, Ring W,Ring X, and Ring Y is an optionally fused 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen and sulfur. Insome embodiments, one or more of Ring V, Ring W, Ring X, and Ring Y isfurther substituted with 1-2 oxo groups.

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is

In some embodiments, Ring V is In some

In some embodiments, Ring V is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring W is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring Y is

In some embodiments, Ring D is N

In some embodiments, Ring V, Ring W, Ring X, and Ring Y is independentlyselected from those depicted in Table 1, below.

As defined above and described herein, in some embodiments, R^(w) isselected from

or hydrogen.

In some embodiments, R^(w) is

In some embodiments, R^(w) is hydrogen.

In some embodiments, R^(w) is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, Ring Z isphenyl, a 5-7 membered saturated or partially unsaturated carbocyclic orheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein Ring Z is further optionally substituted with 1-2 oxogroups.

In some embodiments, Ring Z is phenyl. In some embodiments, Ring Z is a5-7 membered saturated or partially unsaturated carbocyclic orheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring Z is a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, Ring Z isfurther substituted with 1-2 oxo groups.

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is

In some embodiments, Ring Z is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, each ofR^(x) and R^(y) is independently hydrogen, deuterium, R^(z), halogen,—CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CFR₂,—CF₂R, —CF₃, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R, or two R^(x) groups or two R^(y) groupsare optionally taken together to form an optionally substituted 5-7membered partially unsaturated or aryl fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(x) and/or R^(y) is hydrogen. In someembodiments, R^(x) and/or R^(y) is deuterium. In some embodiments, R^(x)and/or R^(y) is R^(z). In some embodiments, R^(x) and/or R^(y) ishalogen. In some embodiments, R^(x) and/or R^(y) is —CN. In someembodiments, R^(x) and/or R^(y) is —NO₂. In some embodiments, R^(x)and/or R^(y) is —OR, In some embodiments, R^(x) and/or R^(y) is —SR, Insome embodiments, R^(x) and/or R^(y) is —NR₂. In some embodiments, R^(x)and/or R^(y) is —SiR₃. In some embodiments, R^(x) and/or R^(y) is—S(O)₂R. In some embodiments, R^(x) and/or R^(y) is —S(O)₂NR₂. In someembodiments, R^(x) and/or R^(y) is —S(O)R. In some embodiments, R^(x)and/or R^(y) is —CFR₂. In some embodiments, R^(x) and/or R^(y) is —CF₂R.In some embodiments, R^(x) and/or R^(y) is —CF₃. In some embodiments,R^(x) and/or R^(y) is —C(O)R. In some embodiments, R^(x) and/or R^(y) is—C(O)OR, In some embodiments, R^(x) and/or R^(y) is —C(O)NR₂. In someembodiments, R^(x) and/or R^(y) is —C(O)N(R)OR, In some embodiments,R^(x) and/or R^(y) is —C(R)₂N(R)C(O)R. In some embodiments, R^(x) and/orR^(y) is —C(R)₂N(R)C(O)N(R)₂. In some embodiments, R^(x) and/or R^(y) is—OC(O)R. In some embodiments, R^(x) and/or R^(y) is —OC(O)N(R)₂. In someembodiments, R^(x) and/or R^(y) is —OP(O)R₂. In some embodiments, R^(x)and/or R^(y) is —OP(O)(OR)₂. In some embodiments, R^(x) and/or R^(y) is—OP(O)(OR)NR₂. In some embodiments, R^(x) and/or R^(y) is —OP(O)(NR₂)₂.In some embodiments, R^(x) and/or R^(y) is —N(R)C(O)OR, In someembodiments, R^(x) and/or R is —N(R)C(O)R. In some embodiments, R^(x)and/or R^(y) is —N(R)C(O)NR₂. In some embodiments, R^(x) and/or R^(y) is—N(R)S(O)₂R. In some embodiments, R^(x) and/or R^(y) is —NP(O)R₂. Insome embodiments, R^(x) and/or R^(y) is —N(R)P(O)(OR)₂. In someembodiments, R^(x) and/or R^(y) is —N(R)P(O)(OR)NR₂. In someembodiments, R^(x) and/or R^(y) is —N(R)P(O)(NR₂)₂. In some embodiments,R^(x) and/or R^(y) is —N(R)S(O)₂R. In some embodiments, two R^(x) groupsor two Ry³ groups are optionally taken together to form an optionallysubstituted 5-7 membered partially unsaturated or aryl fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(y) is —OH.

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is

In some embodiments, R^(x) is methyl.

In some embodiments, R^(x) and R^(y) are selected from those depicted inTable 1, below.

As defined above and described herein, in some embodiments, each R isindependently hydrogen, or an optionally substituted group selected fromC₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or partiallyunsaturated heterocyclic having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same atom are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe atom to which they are attached, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted group selected from C₁₋₆ aliphatic. In someembodiments, R is phenyl. In some embodiments, R is a 4-7 memberedsaturated or partially unsaturated heterocyclic having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R is a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, two R groups on the same atom are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe atom to which they are attached, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, each R^(z)is independently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, R^(z) is an optionally substituted group selectedfrom C₁₋₆ aliphatic. In some embodiments, R^(z) is phenyl. In someembodiments, R^(z) is a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(z) is a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, R^(z) is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, L^(x) is acovalent bond or a C₁₋₃ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein 1-2 methylene units of the chainare independently and optionally replaced with —O—, —C(O)—, —C(S)—,—C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂— or —CR═CR—.

In some embodiments, L^(x) is a covalent bond. In some embodiments,L^(x) is a C₁₋₃ bivalent straight or branched saturated or unsaturatedhydrocarbon chain wherein 1-2 methylene units of the chain areindependently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—,—CF(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂- or —CR═CR—.

In some embodiments, L^(x) is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, x is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, x is 0. In some embodiments, x is 1. In someembodiments, x is 2. In some embodiments, x is 3. In some embodiments, xis 4. In some embodiments, x is 5. In some embodiments, x is 6. In someembodiments, x is 7. In some embodiments, x is 8. In some embodiments, xis 9. In some embodiments, x is 10. In some embodiments, x is 11. Insome embodiments, x is 12. In some embodiments, x is 13. In someembodiments, x is 14. In some embodiments, x is 15. In some embodiments,x is 16.

In some embodiments, x is selected from those depicted in Table 1,below.

As defined above and described herein, in some embodiments, y is 0, 1,2, 4, or 5.

In some embodiments, y is 0. In some embodiments, y is 1. In someembodiments, y is 2. In some embodiments, y is 3. In some embodiments, yis 4. In some embodiments, y is 5.

In some embodiments, y is selected from those depicted in Table 1,below.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, and L^(x) is a covalent bond asshown, to provide a compound of formula I-a-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring V, Ring W, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, and Ring Band Ring C are spiro fused as shown, to provide a compound of formulaI-a-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring V, Ring W, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, and Ring Vis pyridazinyl as shown, to provide a compound of formula I-a-3:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring Y, x, and y is as defined        above and described in embodiments herein, both singly and in        combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, and Ring Vis pyridazinyl as shown, to provide a compound of formula I-a-4:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring Y, x, and y is as defined        above and described in embodiments herein, both singly and in        combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(x) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, Ring V ispyridazinyl, and Ring X and Ring Y are spiro fused as shown, to providea compound of formula I-a-5:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring Y, x, and y is as defined        above and described in embodiments herein, both singly and in        combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is hydrogen, one R is —OH, Ring V is benzo,and L^(x) is a covalent bond as shown, to provide a compound of formulaI-a-6:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), Ring W, Ring Y, and x is as defined above and        described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is hydrogen, one R is —OH, Ring V is benzo,Ring Y is pyridazinyl, and L^(x) is a covalent bond as shown, to providea compound of formula I-a-7:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), Ring W, and x is as defined above and described        in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, Ring V ispyridazinyl, and Ring W is pyrrolyl as shown, to provide a compound offormula I-a-8:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring Y, x, and y is as defined above and        described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-a, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, Ring V ispyridazinyl, and Ring W is piperazinyl as shown, to provide a compoundof formula I-a-9:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring Y, x, and y is as defined above and        described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, and L^(x) is a covalent bond asshown, to provide a compound of formula I-b-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring V, Ring W, Ring X, Ring Y, x, and y        is as defined above and described in embodiments herein, both        singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(w) is

Ring Z is phenyl, one R³ is —OH, L^(x) is a covalent bond, and Ring Xand Ring Y are spiro fused as shown, to provide a compound of formulaI-b-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring V, Ring W, Ring X, Ring Y, x, and y        is as defined above and described in embodiments herein, both        singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, and L^(x) is a covalent bond, andRing V is pyridazinyl as shown, to provide a compound of formula I-b-3:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring X, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(x) is

Ring Z is phenyl, one R^(y) is —OH, and L^(x) is a covalent bond, andRing V is pyridazinyl as shown, to provide a compound of formula I-b-4:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring X, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, Ring V ispyridazinyl, and Ring X and Ring Y are spiro fused as shown, to providea compound of formula I-b-5:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring X, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In certain embodiments, the present invention provides a compound offormula I-b, wherein R^(w) is

Ring Z is phenyl, one R^(y) is —OH, L^(x) is a covalent bond, Ring V ispyridazinyl, and Ring X and Ring Y are spiro fused as shown, to providea compound of formula I-b-6:

-   -   or a pharmaceutically acceptable salt thereof, wherein each of        DIM, L, R^(x), R^(y), Ring W, Ring X, Ring Y, x, and y is as        defined above and described in embodiments herein, both singly        and in combination.

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

In some embodiments, SMARCA is

Ligase Binding Moiety (LBM)

As defined herein and described below, wherein a formula is depictedusing square brackets, e.g,

L is attached to a modifiable carbon, oxygen, or nitrogen atom withinDIM or LBM including substitution or replacement of a defined group inDIM or LBM.

In some embodiments, DIM is LBM. In certain embodiments, the presentinvention provides a compound of formula I, wherein LBM is an E3ubiquitin ligase (cereblon) binding moiety thereby forming a compound offormula I-aa:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described herein, and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or        —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,        —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted        C₁₋₄ aliphatic;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein

-   -   Ring B is a fused ring selected from 6-membered aryl, 6-membered        heteroaryl containing 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or        partially unsaturated carbocyclyl, 5 to 7-membered saturated or        partially unsaturated heterocyclyl with 1-3 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur, or 5-membered heteroaryl with 1-4 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—,        —S—, —S(O)₂— or —(C)═CH—;    -   m is 0, 1, 2, 3 or 4;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)m is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)m may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R group.

In some embodiments, a compound of formula I-aa above is provided as acompound of formula I-aa′ or formula I-aa″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring A, L, L¹, R¹, R², X¹, X², X³, and m is as        defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-bb:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or;

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or        —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,        —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted        C₁₋₄ aliphatic;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein Ring B is other than imidazo or benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

-   -   Ring B is a fused ring selected from 6-membered aryl, 6-membered        heteroaryl containing 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or        partially unsaturated carbocyclyl, 5 to 7-membered saturated or        partially unsaturated heterocyclyl with 1-3 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur, or 5-membered heteroaryl with 1-4 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)m is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)m may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, the compound of formula I-bb above is provided as acompound of formula I-bb′ or formula I-bb″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring A, L, R¹, R², X¹, X², X³, and m is as        defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-cc:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each R² is independently hydrogen, —R, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

-   -   Ring B is a fused ring selected from 6-membered aryl, 6-membered        heteroaryl containing 1-4 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or        partially unsaturated carbocyclyl, 5 to 7-membered saturated or        partially unsaturated heterocyclyl with 1-3 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur, or 5-membered heteroaryl with 1-4 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)m is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)m may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, the compound of formula I-cc above is provided as acompound of formula I-cc′ or formula I-cc″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring A, L, R¹, R², X¹, and m is as defined        above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-dd:

-   -   or a pharmaceutically acceptable salt thereof, wherein, L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or        —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,        —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring C is a mono- or bicyclic ring selected from

-   -   each of R² and R^(3a) is independently hydrogen, deuterium, —R⁶,        halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R,        —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,        —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂,        —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   Ring D is selected from a 6-membered aryl, 6-membered heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, 5 to 7-membered saturated or partially        unsaturated carbocyclyl, 5 to 7-membered saturated or partially        unsaturated heterocyclyl with 1-3 heteroatoms independently        selected from boron, nitrogen, oxygen, silicon, or sulfur, or        5-membered heteroaryl with 1-4 heteroatoms independently        selected from nitrogen, oxygen or sulfur;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)——C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—;    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, 2, 3 or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and        Ring D is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-dd above is provided as acompound of formula I-dd′ or formula I-dd″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X¹, X²,        X³, n, m, and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ee:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:

X¹ is a bivalent moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring C is a mono- or bicyclic ring selected from

-   -   each of R² and R^(3a) is independently hydrogen, —R⁶, halogen,        —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring D is selected from 6-membered aryl, 6-membered heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, 5 to 7-membered saturated or partially        unsaturated carbocyclyl, 5 to 7-membered saturated or partially        unsaturated heterocyclyl with 1-3 heteroatoms independently        selected from boron, nitrogen, oxygen, silicon, or sulfur, or        5-membered heteroaryl with 1-4 heteroatoms independently        selected from nitrogen, oxygen or sulfur;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3 or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring C and        Ring D is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-ee above is provided as acompound of formula I-ee′ or formula I-ee″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring C, Ring D, L, R¹, R², R^(3a), X¹, n, m, and        p is as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ff:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CR₂—, —NR—, —O—, —S—, or        —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R,        —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring C is a mono- or bicyclic ring selected

-   -   each or R² and R^(3a) is independently hydrogen, deuterium, —R⁶,        halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R,        —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,        —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂,        —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   Ring D is selected from 6-membered aryl, 6-membered heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, 5 to 7-membered saturated or partially        unsaturated carbocyclyl, 5 to 7-membered saturated or partially        unsaturated heterocyclyl with 1-3 heteroatoms independently        selected from boron, nitrogen, oxygen, silicon, or sulfur, or        5-membered heteroaryl with 1-4 heteroatoms independently        selected from nitrogen, oxygen or sulfur;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—;    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, 2, 3 or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-ff above is provided as acompound of formula I-ff′ or formula I-ff″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring C, Ring D, L, L¹, R¹, R², R^(3a), X, X²,        X³, m, n, and p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-gg:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:

X¹ is a bivalent moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring C is a mono- or bicyclic ring selected from

-   -   each of R², R^(3a), and R⁴ is independently hydrogen, —R⁶,        halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring D is selected from 6-membered aryl, 6-membered heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, 5 to 7-membered saturated or partially        unsaturated carbocyclyl, 5 to 7-membered saturated or partially        unsaturated heterocyclyl with 1-3 heteroatoms independently        selected from boron, nitrogen, oxygen, silicon, or sulfur, or        5-membered heteroaryl with 1-4 heteroatoms independently        selected from nitrogen, oxygen or sulfur;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-gg above is provided as acompound of formula I-gg′ or formula I-gg″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring C, Ring D, L, R¹, R², R^(3a), X¹, m, n, and        p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-hh:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or

-   -   X² is a carbon atom, nitrogen atom, or silicon atom;    -   X³ is a bivalent moiety selected from a covalent bond, —CR₂—,        —NR—, —O—, —S—, or —SiR₂—;    -   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR,        —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,        —Si(OH)₂R, —Si(OH)R₂, —SiR₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,        —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each of Ring E, Ring F, and Ring G is independently a fused ring        selected from 6-membered aryl, 6-membered heteroaryl containing        1-4 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 5 to 7-membered saturated or partially unsaturated        carbocyclyl, 5 to 7-membered saturated or partially unsaturated        heterocyclyl with 1-3 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered        heteroaryl with 1-4 heteroatoms independently selected from        nitrogen, oxygen or sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—; and    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)m is depicted on Ring E, Ring F, orRing G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)m may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring F or Ring H are fused to Ring G.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring F or Ring H are fused toRing G.

In some embodiments, a compound of formula I-hh above is provided as acompound of formula I-hh′ or formula I-hh″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring E, Ring F, Ring G, L, L¹, R¹, R², X¹, X²,        X³, and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-hh-1 or I-hh-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,        —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each of Ring E, Ring F, and Ring G is independently a fused ring        selected from 6-membered aryl, 6-membered heteroaryl containing        1-4 heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 5 to 7-membered saturated or partially unsaturated        carbocyclyl, 5 to 7-membered saturated or partially unsaturated        heterocyclyl with 1-3 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered        heteroaryl with 1-4 heteroatoms independently selected from        nitrogen, oxygen or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16; and    -   R⁴, R¹⁰, R¹¹, R¹⁵, W¹, W², and X is as defined in WO        2019/099868, the entirety of each of which is herein        incorporated by reference.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)m is depicted on Ring E, Ring F, orRing G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)m may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring F or Ring H are fused to Ring G.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the carbon atom to which Ring F or Ring H are fused toRing G.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ii:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:

X¹ is a bivalent moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each of Ring E, Ring F, and Ring G is independently a fused ring        selected from 6-membered aryl containing 0-3 nitrogens, 5 to        7-membered saturated or partially unsaturated carbocyclyl, 5 to        7-membered saturated or partially unsaturated heterocyclyl with        1-3 heteroatoms independently selected from boron, nitrogen,        oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3        heteroatoms independently selected from nitrogen, oxygen or        sulfur; and    -   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E, Ring F, or Ring G, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring E, Ring F, orRing G, including the ring to which Ring E or Ring G is fused to Ring F.

Where a point of attachment of —(R²)m is depicted on Ring E, Ring F, orRing G, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)m may be at anyavailable carbon or nitrogen atom on Ring E, Ring F, or Ring G includingthe carbon atom to which Ring F or Ring H are fused to Ring G.

In some embodiments, a compound of formula I-ii above is provided as acompound of formula I-ii′ or formula I-ii″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, L, Ring E, Ring F, Ring G, L, R¹, R², X¹, and m        is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-jj:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or;

-   -   X² is a carbon atom, nitrogen atom, or silicon atom;    -   X³ is a bivalent moiety selected from a covalent bond, —CR₂—,        —NR—, —O—, —S—, or —SiR₂—;    -   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR,        —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,        —Si(OH)₂R, —Si(OH)R₂, —SiR₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring E is a fused ring selected from 6-membered aryl, 6-membered        heteroaryl containing 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or        partially unsaturated carbocyclyl, 5 to 7-membered saturated or        partially unsaturated heterocyclyl with 1-3 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur, or 5-membered heteroaryl with 1-4 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   Ring H is a fused ring selected from a 7-9 membered saturated or        partially unsaturated carbocyclyl or heterocyclyl ring with 1-3        heteroatoms independently selected from boron, nitrogen, oxygen,        silicon, or sulfur, wherein Ring E is optionally further        substituted with 1-2 oxo groups;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—;    -   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-jj above is provided as acompound of formula I-jj′ or formula I-jj″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring E, Ring H, L, L¹, R¹, R², X¹, X², X³, and m        is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-kk:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:

X¹ is a bivalent moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or;

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring E is a fused ring selected from 6-membered aryl, 6-membered        heteroaryl containing 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or        partially unsaturated carbocyclyl, 5 to 7-membered saturated or        partially unsaturated heterocyclyl with 1-3 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur, or 5-membered heteroaryl with 1-4 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   Ring H is a ring selected from a 7-9 membered saturated or        partially unsaturated carbocyclyl or heterocyclyl ring with 1-3        heteroatoms independently selected from boron, nitrogen, oxygen,        silicon, or sulfur, wherein Ring E is optionally further        substituted with 1-2 oxo groups; and    -   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring E or Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring E and RingH, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring E or Ring H including thecarbon atom to which Ring E and Ring H are fused.

Where a point of attachment of

is depicted on Ring E and Ring H, it is intended, and one of ordinaryskill in the art would appreciate, that the point of attachment of

may be on any available carbon or nitrogen atom on Ring E or Ring Hincluding the carbon atom to which Ring E and Ring H are fused.

In some embodiments, a compound of formula I-kk above is provided as acompound of formula I-kk′ or formula I-kk″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring E, Ring H, L, R¹, R², X¹, and m is as        defined above.

In some embodiments, the present invention provides the compound offormula I-kk wherein Ring H is 1,3-dihydro-2H-1,4-diazepin-2-one,thereby forming a compound of formula I-kk-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, L, Ring E, X¹, R¹, R², and m is as defined        above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-11:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —CHCF₃—, —SO₂—, —S(O)—, —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—,        —C(S)—, or

-   -   X² is a carbon atom, nitrogen atom, or silicon atom;    -   X³ is a bivalent moiety selected from a covalent bond, —CR₂—,        —NR—, —O—, —S—, or —SiR₂—;    -   R¹ is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR,        —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,        —Si(OH)₂R, —Si(OH)R₂, —SiR₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R, —NP(O)R₂,        —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or        —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each of Ring I and J is independently a fused ring selected from        6-membered aryl, 6-membered heteroaryl containing 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, 5 to 7-membered saturated or partially unsaturated        carbocyclyl, 5 to 7-membered saturated or partially unsaturated        heterocyclyl with 1-3 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered        heteroaryl with 1-4 heteroatoms independently selected from        nitrogen, oxygen or sulfur;    -   Ring K is a fused ring selected from a 7-12 membered saturated        or partially unsaturated carbocyclyl or heterocyclyl ring with        1-3 heteroatoms independently selected from boron, nitrogen,        oxygen, silicon, or sulfur, wherein Ring H is optionally further        substituted with 1-2 oxo groups;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—,        —S(O)₂— or —(C)═CH—; and    -   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R²)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-11 above is provided as acompound of formula I-11′ or formula I-11″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring I, Ring J, Ring K, L, L¹, R¹, R², X¹, X²,        X³, and m is as defined above.

In certain embodiments, the present invention provides a compound offormula I-mm:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein:

X¹ is a bivalent moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, deuterium, —R, halogen, —CN,        —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each of Ring I and J is independently a fused ring selected from        6-membered aryl, 6-membered heteroaryl containing 1-4        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, 5 to 7-membered saturated or partially unsaturated        carbocyclyl, 5 to 7-membered saturated or partially unsaturated        heterocyclyl with 1-3 heteroatoms independently selected from        boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered        heteroaryl with 1-4 heteroatoms independently selected from        nitrogen, oxygen or sulfur;    -   Ring K is a fused ring selected from a 7-12 membered saturated        or partially unsaturated carbocyclyl or heterocyclyl ring with        1-3 heteroatoms independently selected from boron, nitrogen,        oxygen, silicon, or sulfur, wherein Ring H is optionally further        substituted with 1-2 oxo groups; and    -   m is 0, 1, 2, 3, or 4.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

Where a point of attachment of —(R)_(m) is depicted on Ring I, Ring J,and Ring K, it is intended, and one of ordinary skill in the art wouldappreciate, that the point of attachment of —(R²)_(m) may be on anyavailable carbon or nitrogen atom on Ring I, Ring J, or Ring K,including the carbon atom to which Ring I, Ring J, and Ring K are fused.

Where a point of attachment of

is depicted on Ring I, Ring J, and Ring K, it is intended, and one ofordinary skill in the art would appreciate, that the point of attachmentof

may be on any available carbon or nitrogen atom on Ring I, Ring J, orRing K, including the carbon atom to which Ring I, Ring J, and Ring Kare fused.

In some embodiments, a compound of formula I-mm above is provided as acompound of formula I-mm′ or formula I-mm″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, Ring I, Ring J, Ring K, L, R¹, R², X¹, and m is        as defined above.

In some embodiments, the present invention provides the compound offormula I-mm wherein Ring J is pyrrole, thereby forming a compound offormula I-mm-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of SMARCA, L, Ring I, Ring K, X¹, R¹, R², and m is as        defined above.

As described above, in another aspect, the present invention provides acompound of Formula I-nn:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Ring M is selected from

-   -   each of X¹, X⁶, and X⁷ is independently a bivalent moiety        selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,        —P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

-   -   each of X³ and X⁵ is independently a bivalent moiety selected        from a covalent bond, —CR₂—, —NR—, —O—, —S—, and —SiR₂—;    -   X⁴ is a trivalent moiety selected from

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R^(3a) is independently hydrogen, deuterium, —R⁶, halogen,        —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,        —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   each R⁷ is independently hydrogen, deuterium, halogen, —CN, —OR,        —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,        —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally        substituted C₁₋₄ aliphatic; or        -   R⁷ and X¹ or X³ are taken together with their intervening            atoms to form a 5-7 membered saturated, partially            unsaturated, carbocyclic ring or heterocyclic ring having            1-3 heteroatoms, independently selected from boron,            nitrogen, oxygen, silicon, or sulfur;        -   two R⁷ groups on the same carbon are optionally taken            together with their intervening atoms to form a 3-6 membered            spiro fused ring or a 4-7 membered heterocyclic ring having            1-2 heteroatoms independently selected from boron, nitrogen,            oxygen, silicon, or sulfur;        -   two R⁷ groups on adjacent carbon atoms are optionally taken            together with their intervening atoms to form a 3-7 membered            saturated, partially unsaturated, carbocyclic ring or            heterocyclic ring having 1-3 heteroatoms independently            selected from boron, nitrogen, oxygen, silicon, or sulfur,            or a 7-13 membered saturated, partially unsaturated, bridged            heterocyclic ring, or a spiro heterocyclic ring having 1-3            heteroatoms, independently selected from boron, nitrogen,            oxygen, silicon, or sulfur;    -   Ring D is selected from 6 to 10-membered aryl or heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, 5 to 7-membered saturated or partially        unsaturated carbocyclyl, 5 to 7-membered saturated or partially        unsaturated heterocyclyl with 1-3 heteroatoms independently        selected from boron, nitrogen, oxygen, silicon, or sulfur, or        5-membered heteroaryl with 1-4 heteroatoms independently        selected from nitrogen, oxygen or sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—,        —S—, —S(O)₂— or —(C)═CH—;    -   n is 0, 1, 2, 3, or 4; and    -   q is 0, 1, 2, 3, or 4.

As defined above and described herein, each of X¹, X⁶, and X⁷ isindependently a bivalent moiety selected from a covalent bond, —CH₂—,—C(R)₂—, —C(O)—, —C(S)—, —CH(R)—, —CH(CF₃)—, —P(O)(OR)—, —P(O)(R)—,—P(O)(NR₂)—, —S(O)—, —S(O)₂—, or

In some embodiments, each of X¹, X⁶, and X⁷ is independently a covalentbond. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CR₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—C(O)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—C(S)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH(R)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—CH(CF₃)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)(OR)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)(R)—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—P(O)NR₂—. In some embodiments, each of X¹, X⁶, and X⁷ is independently—S(O)—In some embodiments, each of X¹, X⁶, and X⁷ is independently—S(O)₂—. In some embodiments, each of

-   -   X¹, X⁶, and X⁷ is independently

In some embodiments, each of X¹, X⁶, and X⁷ is independently selectedfrom those depicted in Table 1 below.

As defined above and described herein, X² is a carbon atom, nitrogenatom, or silicon atom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is anitrogen atom. In some embodiments, X² is a silicon atom.

In some embodiments, X² is selected from those depicted in Table 1below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂—, —CR₂—, —NR—, —CF₂—, —CHF—, —S—, —CH(R)—, —SiR₂—, or —O—.

In some embodiments, each of X³ and X⁵ is independently —CH₂—. In someembodiments, each of X³ and X⁵ is independently —CR₂—. In someembodiments, each of X³ and X⁵ is independently —NR—. In someembodiments, each of X³ and X⁵ is independently —CF₂—. In someembodiments, each of X³ and X⁵ is independently —CHF—. In someembodiments, each of X³ and X⁵ is independently —S—, In someembodiments, each of X³ and X⁵ is independently —CH(R)—. In someembodiments, each of X³ and X⁵ is independently —SiR₂—. In someembodiments, each of X³ and X⁵ is independently —O—.

In some embodiments, each of X³ and X⁵ is independently selected fromthose depicted in Table 1 below.

As defined above and described herein, X⁴ is a trivalent moiety selectedfrom

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is

In some embodiments, X⁴ is selected from those depicted in Table 1below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)R₂, —SiR₃, an optionally substituted C₁₋₄aliphatic, or R¹ and X¹ or X⁴ are taken together with their interveningatoms to form a 5-7 membered saturated, partially unsaturated,carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR, In some embodiments, R¹ is —SR,In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —P(O)(OR)₂.In some embodiments, R¹ is —P(O)(NR₂)OR, In some embodiments, R¹ is—P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)₂R. In some embodiments,R¹ is —Si(OH)R₂. In some embodiments, R¹ is —SiR₃. In some embodiments,R¹ is an optionally substituted C₁₋₄ aliphatic. In some embodiments, R¹and X¹ or X⁴ are taken together with their intervening atoms to form a5-7 membered saturated, partially unsaturated, carbocyclic ring orheterocyclic ring having 1-3 heteroatoms, independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, R¹ is selected from those depicted in Table 1below.

As defined above and described herein, each R is independently hydrogen,deuterium, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from boron, nitrogen,oxygen, silicon, and sulfur, or two R groups on the same nitrogen aretaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is deuterium.In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is optionally substituted phenyl. In some embodiments, Ris optionally substituted 4-7 membered saturated or partiallyunsaturated heterocyclic having 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments,R is optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As defined above and described herein, each of R² and R^(3a) isindependently hydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR,—Si(OH)₂R, —Si(OH)R₂, —SR, —NR₂, —SiR₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R.

In some embodiments, R² and/or R^(3a) is hydrogen. In some embodiments,R² and/or R^(3a) is deuterium. In some embodiments, R² and/or R^(3a) is—R⁶. In some embodiments, R² and/or R^(3a) is halogen. In someembodiments, R² and/or R^(3a) is —CN. In some embodiments, R² and/orR^(3a) is —NO₂. In some embodiments, R² and/or R^(3a) is —OR, In someembodiments, R² and/or R^(3a) is —Si(OH)₂R. In some embodiments, R²and/or R^(3a) is —Si(OH)R₂. In some embodiments, R² and/or R^(3a) is—SR, In some embodiments, R² and/or R^(3a) is —NR₂. In some embodiments,R² and/or R^(3a) is —SiR₃. In some embodiments, R² and/or R^(3a) is—S(O)₂R. In some embodiments, R² and/or R^(3a) is —S(O)₂NR₂. In someembodiments, R² and/or R^(3a) is —S(O)R. In some embodiments, R² and/orR^(3a) is —C(O)R. In some embodiments, R² and/or R^(3a) is —C(O)OR, Insome embodiments, R² and/or R^(3a) is —C(O)NR₂. In some embodiments, R²and/or R^(3a) is —C(O)N(R)OR, In some embodiments, R² and/or R^(3a) is—C(R)₂N(R)C(O)R. In some embodiments, R² and/or R^(3a) is—C(R)₂N(R)C(O)NR₂. In some embodiments, R² and/or R^(3a) is —OC(O)R. Insome embodiments, R² and/or R^(3a) is —OC(O)NR₂. In some embodiments, R²and/or R^(3a) is —OP(O)R₂. In some embodiments, R² and/or R^(3a) is—OP(O)(OR)₂. In some embodiments, R² and/or R^(3a) is —OP(O)(OR)NR₂. Insome embodiments, R² and/or R^(3a) is —OP(O)(NR₂)₂—. In someembodiments, R^(z) and/or R^(3a) is —N(R)C(O)OR, In some embodiments, R²and/or R^(3a) is —N(R)C(O)R. In some embodiments, R² and/or R^(3a) is—N(R)C(O)NR₂. In some embodiments, R² and/or R^(3a) is —NP(O)R₂. In someembodiments, R² and/or R^(3a) is —N(R)P(O)(OR)₂. In some embodiments, R²and/or R^(3a) is —N(R)P(O)(OR)NR₂. In some embodiments, R² and/or R^(3a)is —N(R)P(O)(NR₂)₂. In some embodiments, R² and R^(3a) is independently—N(R)S(O)₂R.

In some embodiments, R² and/or R^(3a) is —OH. In some embodiments, R²and/or R^(3a) is —NH₂. In some embodiments, R² and/or R^(3a) is —CH₂NH₂.In some embodiments, R² and/or R^(3a) is —CH₂NHCOMe. In someembodiments, R² and/or R^(3a) is —CH₂NHCONHMe. In some embodiments, R²and/or R^(3a) is —NHCOMe. In some embodiments, R² and/or R^(3a) is—NHCONHEt. In some embodiments, R² and/or R^(3a) is —SiMe₃. In someembodiments, R² and/or R^(3a) is —SiMe₂OH. In some embodiments, R²and/or R^(3a) is —SiMe(OH)₂. In some embodiments R² and/or R^(3a) is

In some embodiments, R² and/or R^(3a) is Br. In some embodiments, R²and/or R^(3a) is Cl. In some embodiments, R² and/or R^(3a) is F. In someembodiments, R² and/or R^(3a) is Me. In some embodiments, R² and/orR^(3a) is —NHMe. In some embodiments, R² and/or R^(3a) is —NMe₂. In someembodiments, R² and/or R^(3a) is —NHCO₂Et. In some embodiments, R²and/or R^(3a) is —CN. In some embodiments, R² and/or R^(3a) is —CH₂Ph.In some embodiments, R² and/or R^(3a) is —NHCO₂tBu. In some embodiments,R² and/or R^(3a) is —CO₂tBu. In some embodiments, R² and/or R^(3a) is—OMe. In some embodiments, R² and/or R^(3a) is —CF₃.

In some embodiments, R² and R^(3a) are selected from those depicted inTable 1, below.

As defined above and described herein, R³ is hydrogen, deuterium,halogen, —CN, —NO₂, —OR, —NR₂, —SR, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)NR(OR), —OC(O)R, —OC(O)NR₂, —OP(O)(OR)₂,—OP(O)(NR₂)₂, —OP(O)(OR)NR₂, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)NR₂,—N(R)S(O)₂R, —N(R)S(O)₂NR₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, or—Si(R)₃.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is halogen. In some embodiments, R³is —CN. In some embodiments, R³ is —NO₂. In some embodiments, R³ is —OR,In some embodiments, R³ is —NR₂. In some embodiments, R³ is —SR, In someembodiments, R³ is —S(O)₂R. In some embodiments, R³ is —S(O)₂NR₂. Insome embodiments, R³ is —S(O)R. In some embodiments, R³ is —C(O)R. Insome embodiments, R³ is —C(O)OR, In some embodiments, R³ is —C(O)NR₂. Insome embodiments, R³ is —C(O)NR(OR). In some embodiments, R³ is —OC(O)R.In some embodiments, R³ is —OC(O)NR₂. In some embodiments, R³ is—OP(O)(OR)₂. In some embodiments, R³ is —OP(O)(NR₂)₂. In someembodiments, R³ is —OP(O)(OR)NR₂. In some embodiments, R³ is —N(R)C(O)R.In some embodiments, R³ is —N(R)C(O)OR, In some embodiments, R³ is—N(R)C(O)NR₂. In some embodiments, R³ is —N(R)S(O)₂R. In someembodiments, R³ is —N(R)S(O)₂NR₂. In some embodiments, R³ is—N(R)P(O)(OR)₂. In some embodiments, R³ is —N(R)P(O)(OR)NR₂. In someembodiments, R³ is —P(O)(OR)₂. In some embodiments, R³ is —P(O)(NR₂)OR,In some embodiments, R³ is —P(O)(NR₂)₂. In some embodiments, R³ is—Si(OH)₂R. In some embodiments, R³ is —Si(OH)(R)₂. In some embodiments,R³ is —Si(R)₃.

In some embodiments, R³ is methyl. In some embodiments, R³ is —OCH₃. Insome embodiments, R³ is chloro.

In some embodiments, R³ is selected from those depicted in Table 1.

As defined above and described herein, each R⁴ is independentlyhydrogen, deuterium, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,—S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—P(O)(OR)₂, —P(O)(NR₂)OR, or —P(O)(NR₂)₂.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is —R⁶. Insome embodiments, R⁴ is halogen. In some embodiments, R⁴ is —CN. In someembodiments, R⁴ is —NO₂. In some embodiments, R⁴ is —OR, In someembodiments, R⁴ is —SR, In some embodiments, R⁴ is —NR₂. In someembodiments, R⁴ is —S(O)₂R. In some embodiments, R⁴ is —S(O)₂NR₂. Insome embodiments, R⁴ is —S(O)R. In some embodiments, R⁴ is —C(O)R. Insome embodiments, R⁴ is —C(O)OR, In some embodiments, R⁴ is —C(O)NR₂. Insome embodiments, R⁴ is —C(O)N(R)OR, In some embodiments, R⁴ is —OC(O)R.In some embodiments, R⁴ is —OC(O)NR₂. In some embodiments, R⁴ is—N(R)C(O)OR, In some embodiments, R⁴ is —N(R)C(O)R. In some embodiments,R⁴ is —N(R)C(O)NR₂. In some embodiments, R⁴ is —N(R)S(O)₂R. In someembodiments, R⁴ is —P(O)(OR)₂. In some embodiments, R⁴ is —P(O)(NR₂)OR.In some embodiments, R⁴ is —P(O)(NR₂)₂.

In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. Insome embodiments, R⁴ is cyclopropyl.

In some embodiments, R⁴ is selected from those depicted in Table 1.

As defined above and described herein, R⁵ is hydrogen, deuterium, anoptionally substitute C₁₋₄aliphatic, or —CN.

In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ isdeuterium. In some embodiments, R⁵ is an optionally substituted C₁₋₄aliphatic. In some embodiments, R⁵ is —CN.

In some embodiments, R⁵ is selected from those depicted in Table 1.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁶ is an optionally substituted phenyl. In someembodiments, R⁶ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, andsulfur. In some embodiments, R⁶ is an optionally substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1.

As defined generally above, each R⁷ is independently hydrogen,deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(R)₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R, —SiR₃, oran optionally substituted C₁₋₄ aliphatic, or R¹ and X¹ or X³ are takentogether with their intervening atoms to form a 5-7 membered saturated,partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or two R⁷ groups on the same carbon are optionallytaken together with their intervening atoms to form a 3-6 membered spirofused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or two R⁷ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or a 7-13 membered saturated, partially unsaturated,bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ isdeuterium. In some embodiments, R⁷ is halogen. In some embodiments, R⁷is —CN. In some embodiments, R⁷ is —OR, In some embodiments, R⁷ is —SR,In some embodiments, R⁷ is —S(O)R. In some embodiments, R⁷ is —S(O)₂R.In some embodiments, R⁷ is —NR₂. In some embodiments, R⁷ is —Si(R)₃. Insome embodiments, R⁷ is —P(O)(R)₂. In some embodiments, R⁷ is—P(O)(OR)₂. In some embodiments, R⁷ is —P(O)(NR₂)OR, In someembodiments, R⁷ is —P(O)(NR₂)₂. In some embodiments, R⁷ is —Si(OH)R₂. Insome embodiments, R⁷ is —Si(OH)₂R. In some embodiments, R⁷ is anoptionally substituted C₁₋₄ aliphatic. In some embodiments, R⁷ and X¹ orX³ are taken together with their intervening atoms to form a 5-7membered saturated, partially unsaturated, carbocyclic ring orheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R⁷groups on the same carbon are optionally taken together with theirintervening atoms to form a 3-6 membered spiro fused ring or a 4-7membered heterocyclic ring having 1-2 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments,two R¹ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, two R⁷ groups on adjacentcarbon atoms are optionally taken together with their intervening atomsto form a 7-13 membered saturated, partially unsaturated, bridgedheterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms,independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R⁷ is selected from hydrogen, halogen, —CN, —OR,—NR₂, or C₁₋₄ alkyl. In some embodiments, R⁷ is selected from hydrogen,halogen, —CN, or C₁₋₄ alkyl. In some embodiments, R⁷ is fluoro. In someembodiments, two R⁷ groups on the same carbon are optionally takentogether with their intervening atoms to form a 3- or 4-membered spirofused ring.

In some embodiments, R⁷ is selected from those depicted in Table 1below.

As defined above and described herein, Ring A is a bi- or tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1below.

As defined above and described herein, Ring B is a fused ring selectedfrom 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur;

In some embodiments, Ring B is a fused 6-membered aryl. In someembodiments, Ring B is a fused 6-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is a fused 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, Ring B is fused5 to 7-membered saturated or partially saturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, Ring B is fused 5-memberedheteroaryl with 1-4 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, each Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is selected from those depicted in Table 1below.

As defined above and described herein, Ring C is a mono- or bicyclicring selected from

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is

In some embodiments, Ring C is a mono- or bicyclic ring selected from

In some embodiments, Ring C is selected from those depicted in Table 1below.

As defined above and described herein, Ring D is a ring selected from 6to 10-membered aryl or heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, 5 to 7-memberedsaturated or partially unsaturated carbocyclyl, 5 to 7-memberedsaturated or partially unsaturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or 5-membered heteroaryl with 1-4 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur;

In some embodiments, Ring D is a 6 to 10-membered aryl. In someembodiments, Ring D is a 6 to 10-membered heteroaryl containing 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring D is a 5 to 7-membered saturated or partiallyunsaturated carbocyclyl. In some embodiments, Ring D is 5 to 7-memberedsaturated or partially saturated heterocyclyl with 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, Ring D is 5-membered heteroaryl with 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, Ring D is quinoline. In some embodiments, Ring D isisoquinoline. In some embodiments, Ring D is imidazo[1,2-a]pyridine.

In some embodiments, Ring D is selected from those depicted in Table 1below.

As defined above and described herein, each of Ring E, Ring F, and RingG is independently a fused ring selected from 6-membered aryl,6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, each of Ring E, Ring F, and Ring G is independentlya fused ring selected from 6-membered aryl. In some embodiments, each ofRing E, Ring F, and Ring G is independently a fused ring selected from6-membered heteroaryl containing 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, each of Ring E,Ring F, and Ring G is independently a fused ring selected from a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring E, Ring F, and Ring G is independently a fusedring selected from a 5 to 7-membered saturated or partially unsaturatedheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur. In some embodiments, each of RingE, Ring F, and Ring G is independently a fused ring selected from a5-membered heteroaryl with 1-4 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, Ring F is

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently is

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, each of Ring E and Ring G is independently

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiment, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is

In some embodiments, Ring E, Ring F, and Ring G is selected from thosedepicted in Table 1, below.

As defined above and described herein, Ring H is a ring selected from a7-9 membered saturated or partially unsaturated carbocyclyl orheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, wherein Ring E isoptionally further substituted with 1-2 oxo groups.

In some embodiments, Ring H is a ring selected from a 7-9 memberedsaturated or partially unsaturated carbocyclyl or heterocyclyl ring with1-3 heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, wherein Ring H is optionally further substitutedwith 1-2 oxo groups.

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is

In some embodiments, Ring H is selected from those depicted in Table 1,below.

In some embodiments, Ring E and Ring H is

As defined above and described herein, each of Ring I and Ring J isindependently a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur, or 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen or sulfur

In some embodiments, each of Ring I and Ring J is independently a6-membered aryl. In some embodiments, each of Ring I and Ring J isindependently a 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated carbocyclyl. In someembodiments, each of Ring I and Ring J is independently a 5 to7-membered saturated or partially unsaturated heterocyclyl with 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, each of Ring I and Ring J isindependently a 5-membered heteroaryl with 1-3 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, each of Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently is

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is independently

In some embodiments, Ring I and Ring J is selected from those depictedin Table 1, below.

As defined above and described herein, Ring K is a fused ring selectedfrom a 7-12 membered saturated or partially unsaturated carbocyclyl orheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionallyfurther substituted with 1-2 oxo groups.

In some embodiments, Ring K is a fused ring selected from a 7-12membered saturated or partially unsaturated carbocyclyl. In someembodiments, Ring K is a 7-12 membered saturated or partiallyunsaturated heterocyclyl ring with 1-3 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, Ring K is optionally further substituted with 1-2 oxogroups.

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is

In some embodiments, Ring K is selected from those depicted in Table 1below.

In some embodiments, Ring I, Ring J, and Ring K is

As defined above and described herein, Ring M is selected from

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is

In some embodiments, Ring M is selected from those depicted in Table 1below.

As defined above and described here, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —C(O)—, —C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—,—N(R)—, —S—, —S(O)₂— or —(C)═CH—;

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₃ aliphatic. In some embodiments, L¹ is —CH₂—. In some embodiments,L¹ is —C(D)(H)—. In some embodiments, L¹ is —C(D)₂—. In someembodiments, L¹ is —CH₂CH₂—. In some embodiments, L¹ is —NR—. In someembodiments, L¹ is —CH₂NR—. In some embodiments, L¹ is or —O—. In someembodiments, L¹ is —CH₂O—. In some embodiments, L¹ is —S—, In someembodiments, L¹ is —OC(O)—. In some embodiments, L¹ is —C(O)O—. In someembodiments, L¹ is —C(O)—. In some embodiments, L¹ is —S(O)—. In someembodiments, L¹ is —S(O)₂—. In some embodiments, L¹ is —NRS(O)₂—. Insome embodiments, L¹ is —S(O)₂NR—. In some embodiments, L¹ is —NRC(O)—.In some embodiments, L¹ is —C(O)NR—.

In some embodiments, Ring L is selected from those depicted in Table 1below.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In some embodiments,

is selected from those depicted in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1 below.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In some embodiments, n is selected from those depicted in Table 1 below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1 below.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1 below.

In some embodiments, LBM is an E3 ligase ligand well known to one ofordinary skill in the art including those described in M. Toure, C. M.Crews, Angew. Chem. Int. Ed. 2016, 55, 1966, T. Uehara et al. NatureChemical Biology 2017, 13, 675, WO 2017/176708, US 2017/0281784, WO2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, US2019/0076540, WO 2017/197046, US 2019/0076542, WO 2017/197051, US2019/0076539, WO 2017/197055, US 2019/0076541, and WO 2017/197056, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-oo-1, I-oo-2, I-oo-3,I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, or I-oo-10 respectively:

-   -   or a compound of formula I-oo′-1, I-oo′-2, I-oo′-3, I-oo′-4,        I-oo′-5, I-oo′-6, I-oo′-7, I-oo′-8, I-oo′-9, or I-oo′-10        respectively:

-   -   or a compound of formula I-oo″-1, I-oo″-2, I-oo″-3, I-oo″-4,        I-oo″-5, I-oo″-6, I-oo″-7, I-oo″-8, I-oo″-9, or I-oo″-10        respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables

X, X₁, X₂, Y, R₁, R₃, R₃′, R₄, R₅, t, m and n is as defined anddescribed in WO 2017/007612 and US 2018/0134684, the entirety of each ofwhich is herein incorporated by reference.

Accordingly in some embodiments, the present invention provides acompound of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6,I-oo-7, I-oo-8, I-oo-9, I-oo-10, I-oo′-1, I-oo′-2, I-oo′-3, I-oo′-4,I-oo′-5, I-oo′-6, I-oo′-7, I-oo′-8, I-oo′-9, I-oo′-10, I-oo″-1, I-oo″-2,I-oo″-3, I-oo″-4, I-oo″-5, I-oo″-6, I-oo″-7, I-oo″-8, I-oo″-9, orI-oo″-10, or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is a bond, Y₁, O, NH, NR₂, C(O)O, OC(O), C(O)NR₂′, NR₂′C(O),        Y₁—O, Y₁—NH, Y₁—NR₂, Y₁—C(O), Y₁—C(O)O, Y₁—OC(O), Y₁—C(O)NR₂′,        or Y₁—NR₂′C(O), wherein Y₁ is C₁-C₆ alkylene, C₂-C₆ alkenylene,        or C₂-C₆ alkynylene;    -   X is C(O) or C(R₃)₂;    -   X₁—X₂ is C(R₃)═N or C(R₃)₂—C(R₃)₂; each R₁ is independently        halogen, nitro, NH₂, OH, C(O)OH, C₁-C₆ alkyl, or C₁-C₆ alkoxy;    -   R₂ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₅ cycloalkyl, 3- to        8-membered heterocycloalkyl, C(O)—C₁-C₆ alkyl, C(O)—C₂-C₆        alkenyl, C(O)—C₃-C₅ cycloalkyl, or C(O)-3- to 8-membered        heterocycloalkyl, and R₂ is optionally substituted with one or        more of halogen, N(R_(a))₂, NHC(O)R_(a), NHC(O)OR_(a), OR_(b),        C₃-C₅ cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀        aryl, or 5- to 10-membered heteroaryl, wherein each of the C₃-C₅        cycloalkyl, 3- to 8-membered heterocycloalkyl, C₆-C₁₀ aryl or 5-        to 10-membered heteroaryl is optionally further substituted with        one or more of halogen, NH₂, CN, nitro, OH, C(O)OH, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;    -   R₂′ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₅ cycloalkyl, or 3- to        8-membered heterocycloalkyl, and R₂′, when not being H, is        optionally substituted with one or more of halogen, N(R_(a))₂,        NHC(O)R_(a), NHC(O)OR_(a), OR_(b), C₃-C₅ cycloalkyl, 3- to        8-membered heterocycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered        heteroaryl, wherein each of the C₃-C₅ cycloalkyl, 3- to        8-membered heterocycloalkyl, C₆-C₁₀ aryl or 5- to 10-membered        heteroaryl is optionally further substituted with one or more of        halogen, NH₂, CN, nitro, OH, C(O)OH, C₁-C₆ alkyl, C₁-C₆        haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;    -   each R₃ is independently H or C₁-C₃ alkyl optionally substituted        with C₆-C₁₀ aryl or 5- to 10-membered heteroaryl;    -   each R₃′ is independently C₁-C₃ alkyl;    -   each R₄ is independently H or C₁-C₃ alkyl; or two R₄, together        with the carbon atom to which they are attached, form C(O), a        C₃-C₆ carbocycle, or a 4-, 5-, or 6-membered heterocycle        comprising 1 or 2 heteroatoms selected from N and O;    -   R₅ is H, C₁-C₃ alkyl, F, or C₁;    -   each R_(a) independently is H or C₁-C₆ alkyl;    -   R_(b) is H or tosyl;    -   t is 0 or 1;    -   m is 0, 1, 2 or 3; and    -   n is 0, 1 or 2.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-pp-1, I-pp-2, I-pp-3,I-pp-4, I-pp-5, or I-pp-6 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables A, G, G′, Q₁, Q₂, Q₃˜, Q₄, R,        R′, W, X, Y, Z,        , and n is as defined and described in WO 2016/197114 and US        2018/0147202, the entirety of each of which is herein        incorporated by reference.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1 below.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-qq-1, I-qq-2, or I-qq-3respectively.

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described herein, and wherein        each of the variables R¹, R², R⁴, R⁵, R¹⁰, R¹¹, R¹⁴, R¹⁷, W¹,        W², X,        , and n is as defined in WO 2017/197051 which is herein        incorporated by reference in its entirety and wherein

is attached to R¹, the ring formed by combining R¹ and R², or R¹⁷ at thesite of attachment of R¹² as defined in WO 2017/197051 such that

takes the place of the R¹² substituent.

In some embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-rr-1, I-rr-2, I-rr-3, orI-rr-4, respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described herein, and wherein        each of the variables R¹, R⁴, R¹ ⁰, R¹¹, R¹⁴, R¹⁶, W¹, W², X,        , and n is as defined in        WO 2018/237026, the entirety of each of which is herein        incorporated by reference, and wherein

is attached to R¹ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In some embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ss-1 or I-ss-3,respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described herein, and wherein        each of the variables R¹, R¹⁴, and R¹⁶ is as defined in WO        2018/237026, the entirety of each of which is herein        incorporated by reference, and wherein

is attached to R¹ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-tt-1, I-tt-2, I-tt-3,I-tt-4, I-tt-5, I-tt-6, I-tt-7, or I-tt-8:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables Ar, R¹, R², R³, R⁴, R, R⁶, R⁷,        R⁸, A, L, x, y, and        is as described and defined in WO 2017/161119, the entirety of        each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-uu:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables A, B, C, W, X, Y, and Z is as        described and defined in U.S. Pat. No. 5,721,246, the entirety        of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-vv:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R₁, R₂, and n is as described        and defined in WO 2019/043214, the entirety of each of which is        herein incorporated by reference.

In some embodiments, LBM is a IAP E3 Ubiquitin ligase binding moietyrecited in Varfolomeev, E. et al., IAP Antagonists InduceAutoubiquitination of c-IAPs, NF-κB activation, and TNFα-DependentApoptosis, Cell, 2007, 131(4): 669-81, such as, for example:

-   -   wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-ww-1, I-ww-2, I-ww-3, I-ww-4, orI-ww-5 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R¹¹, R^(2′), R^(3′), X, and X¹        is as defined and described in WO 2013/106643 and US        2014/0356322, the entirety of each of which is herein        incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-xx-1, I-xx-2, I-xx-3, I-xx-4,I-xx-5 or I-xx-6 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R^(1′), R^(2′), R^(3′), R₅,        R₆, R₇, R₉, R₁₀, R₁₁, R₁₄, R₁₅, R₁₆, R₁₇, R₂₃, R₂₅, E, G, M, X,        X′, Y, Z₁, Z₂, Z₃, Z₄, and o is as defined and described in WO        2016/149668 and US 2016/0272639, the entirety of each of which        is herein incorporated by reference.

As used herein, depiction of brackets around any LBM

means that the

moiety is covalently attached to said LBM at any available modifiablecarbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and byway of example, such available modifiable carbon, nitrogen, oxygen, orsulfur atoms in the following LBM compound structure are depicted below,wherein each wavy bond defines the point of attachment to said

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-yy-1, I-yy-2, or I-yy-3respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R^(p), R₉, R₁₀, R₁₁, R_(14a),        R_(14b), R₁₅, R₁₆, W³, W⁴, W⁵, X¹, X², and o is as defined and        described in WO 2016/118666 and US 2016/0214972, the entirety of        each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase bindingmoiety thereby forming a compound of formula I-zz-1, I-zz-2, I-zz-3,I-zz-4, I-zz-5, I-zz-6, or I-zz-7 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables A¹, A², A³, R⁵, G and Z is as        defined and described in WO 2017/176958.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-zz′-1, I-zz″-1, I-zz′-2,I-zz′-2, I-zz′-3, I-zz″-3, I-zz′-4, I-zz″-4, I-zz′-7 or I-zz″-7respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables A¹, A², A³, R⁵, G and Z is as        defined and described in WO 2017/176958, the entirety of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3ligase binding moiety thereby forming a compound of formula I-aaa-1,I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9,I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16,I-aaa-17, or I-aaa-18 respectively.

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R₁, R₂, R₃, R₄, R₅, R₆, R₇,        R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,        R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇, R₂₈, R_(1′), R_(2′), R_(3′),        R_(4′), R_(5′), R_(6′), R_(7′), R_(8′), R_(9′), R_(10′),        R_(11′), R_(12′), R_(1″), A, A′, A″, X, Y, and Z is as defined        and described in WO 2017/011371 and US 2017/0008904, the        entirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an IAP E3 ubiquitin ligase binding moietythereby forming a compound of formula I-bbb-1, I-bbb-2, I-bbb-3, orI-bbb-4 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R¹, R², R³, R⁴, R⁵, R⁶, and        R⁷, is as defined and described in WO 2017/011590 and US        2017/0037004, the entirety of each of which is herein        incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3ubiquitin ligase binding moiety; thereby forming a compound of formulaI-ccc-1, I-ccc-2, or I-ccc-3:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA is as defined above and described in embodiments herein,        and wherein:    -   each of X¹, X^(2a), and X^(3a) is independently a bivalent        moiety selected from a covalent bond, —CH₂—, —C(O)—,—C(S)—, or

-   -   each of X^(4a) and X^(5a) is independently a bivalent moiety        selected from —CH₂—, —C(O)—, —C(S)—, or

-   -   R¹; is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each of R², R^(3b), and R^(4a) is independently hydrogen, —R⁶,        halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R^(5a) is hydrogen or C₁₋₆ aliphatic;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A^(a) is a fused ring selected from 6-membered aryl        containing 0-2 nitrogen atoms, 5 to 7-membered partially        saturated carbocyclyl, 5 to 7-membered partially saturated        heterocyclyl with 1-2 heteroatoms independently selected from        nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3        heteroatoms independently selected from nitrogen, oxygen or        sulfur;    -   Ring B^(a) is selected from 6-membered aryl containing 0-2        nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   Ring C^(a) is a selected from 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   m is 0, 1, 2, 3 or 4;    -   o is 0, 1, 2, 3 or 4;    -   q is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I-ccc-1, wherein LBM is an E3 ubiquitin ligase (cereblon)binding moiety thereby forming a compound of formula I-ccc′-1 orI-ccc″-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein SMARCA,        L, Ring A^(a), X¹, X^(2a), X^(3a), R¹, R² and m are as described        above.

As defined above and described herein, each of X¹, X^(2a), and X^(3a) isindependently a bivalent moiety selected from a covalent bond, —CH₂—,—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is selected from those depicted in Table 1,below.

In some embodiments, X^(2a) is a covalent bond, —CH₂—, —C(O)—, —C(S)—,or

In some embodiments, X^(2a) is selected from those depicted in Table 1,below.

In some embodiments, X^(3a) is a covalent bond, —CH₂—, —C(O)—, —C(S)—,or

In some embodiments, X^(3a) is selected from those depicted in Table 1,below.

As defined above and described herein, each of X⁴ and X⁵ isindependently a bivalent moiety selected from —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(4a) is selected from those depicted in Table 1,below.

In some embodiments, X^(5a) is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X^(5a) is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR,—S(O)R, —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R², R^(3b), and R^(4a) isindependently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

In some embodiments, R² is hydrogen, —R, halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R² is selected from those depicted in Table 1,below.

In some embodiments, R^(3b) is hydrogen, —R, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(3b) is methyl.

In some embodiments, R^(3b) is selected from those depicted in Table 1,below.

In some embodiments, R^(4a) is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R^(4a) is methyl.

In some embodiments, R^(4a) is selected from those depicted in Table 1,below.

As defined above and described herein, R^(a) is hydrogen or C₁₋₆aliphatic.

In some embodiments, R^(1a) is t-butyl.

In some embodiments, R^(1a) is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R⁶ is an optionally substituted phenyl. Insome embodiments, R⁶ is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁶ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A^(a) is a fused ringselected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to7-membered partially saturated carbocyclyl, 5 to 7-membered partiallysaturated heterocyclyl with 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments Ring A^(a) is a fused 6-membered aryl containing 0-2nitrogen atoms. In some embodiments Ring A^(a) is a fused 5 to7-membered partially saturated carbocyclyl. In some embodiments RingA^(a) is a fused 5 to 7-membered partially saturated heterocyclyl with1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.In some embodiments Ring A^(a) is a fused 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring A^(a) is a fused phenyl.

In some embodiments, Ring A^(a) is selected from those depicted in Table1, below.

As defined above and described herein, Ring B^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring B^(a) is a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B^(a) is

In some embodiments, Ring B^(a) is selected from those depicted in Table1, below.

As defined above and described herein, Ring C^(a) is selected from6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroarylwith 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, Ring C^(a) is a 6-membered aryl containing 0-2nitrogen atoms. In some embodiments, Ring C^(a) is a 5-memberedheteroaryl with 1-3 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, Ring C^(a) is

In some embodiments, Ring C^(a) is selected from those depicted in Table1, below.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments, m is selected from those depicted in Table 1,below.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, o is 0, 1, 2, 3 or 4.

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2. In some embodiments, o is 3. In some embodiments, ois 4.

In some embodiments, o is selected from those depicted in Table 1,below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are optionally taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. Insome embodiments, R is a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form a 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ddd:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R₉, R₁₀, R₁₁, R¹ _(4a), and        R₁₅ is as described and defined in WO 2017/030814, WO        2016/118666, and US 2017/0327469, the entirety of each of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-eee-1 or I-eee-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables X, W, R₉, R₁₀, R₁₁, R¹ _(4a),        and R_(14b), R₁₅, R¹⁶, and o is as described and defined in WO        2017/030814, WO 2016/118666, and US 2017/0327469, the entirety        of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an IAP binding moiety thereby forming acompound of formula I-fff:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables W, Y, Z, R¹, R², R³, R⁴, and        R⁵ is as described and defined in WO 2014/044622, US        2015/0225449. WO 2015/071393, and US 2016/0272596, the entirety        of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a MDM2 binding moiety thereby forming acompound of formula I-ggg:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        as described and defined in Hines, J. et al., Cancer Res. (DOI:        10.1158/0008-5472.CAN-18-2918), the entirety of each of which is        herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF16 binding moiety thereby forming acompound of formula I-hhh:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        as described and defined in Zhang, X. et al., bioRxiv (doi:        https://doi.org/10.1101/443804), the entirety of each of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF114 binding moiety thereby forming acompound of formula I-iii:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        as described and defined in Spradin, J. N. et al., bioRxiv (doi:        https://doi.org/10.1101/436998), the entirety of each of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF4 binding moiety thereby forming acompound of formula I-jjj:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        as described and defined in Ward, C. C., et al., bioRxiv (doi:        https://doi.org/10.1101/439125), the entirety of each of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-nnn-1 or I-nnn-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R¹, R², R³, X, and Y is as        defined and described in WO 2019/084026, the entirety of each of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety thereby forming acompound of formula I-ooo-1 or I-ooo-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        and wherein each of the variables R¹, R³, and Y is as defined        and described in WO 2019/084030, the entirety of each of which        is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a E3 ubiquitin ligase (cereblon) bindingmoiety thereby forming a compound of formula I-ppp-1, I-ppp-2, I-ppp-3,or I-ppp-4:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described herein, and wherein        each of the variables R⁴, R¹°, R¹¹, R¹, R¹⁶, R¹⁷, W¹, W², and X        is as defined in WO 2019/099868 which is herein incorporated by        reference in its entirety, and wherein

is attached to R¹⁷ or R¹⁶ at the site of attachment of R¹² as defined inWO 2018/237026, such that

takes the place of the R¹² substituent.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-qqq:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        wherein:    -   each X¹ is independently —CH₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

-   -   X² and X³ are independently —CH₂—, —C(O)—, —C(S)—, or

-   -   Z¹ and Z² are independently a carbon atom or a nitrogen atom;    -   Ring A is a fused ring selected from benzo, a 4-6 membered        saturated or partially unsaturated carbocyclic or heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur;    -   L¹ is a covalent bond or a C₁₋₃ bivalent straight or branched        saturated or unsaturated hydrocarbon chain wherein 1-2 methylene        units of the chain are independently and optionally replaced        with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—, —NR—, or        —S(O)₂—;    -   each R¹ is independently selected from hydrogen, deuterium, R⁴,        halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —CF₂R, —CR₂F, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃;        or        -   two R¹ groups are optionally taken together to form an            optionally substituted 5-8 membered partially unsaturated or            aryl fused ring having 0-2 heteroatoms independently            selected from nitrogen, oxygen, or sulfur;    -   each R is independently selected from hydrogen, or an optionally        substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7        membered saturated or partially unsaturated heterocyclic having        1-2 heteroatoms independently selected from nitrogen, oxygen,        and sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same carbon or nitrogen are optionally            taken together with their intervening atoms to form an            optionally substituted 4-7 membered saturated, partially            unsaturated, or heteroaryl ring having 0-3 heteroatoms, in            addition to the carbon or nitrogen, independently selected            from nitrogen, oxygen, and sulfur;    -   R² is selected from

or hydrogen;

-   -   Ring B is phenyl, a 4-10 membered saturated or partially        unsaturated mono- or bicyclic carbocyclic or heterocyclic ring        having 1-3 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, wherein Ring B is further optionally substituted with        1-2 oxo groups;    -   each R³ is independently selected from hydrogen, deuterium, R⁴,        halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂,        —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,        —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂,        —OP(O)(NR₂)₂, and —SiR₃;    -   each R⁴ is independently selected from an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   is a single or double bond;    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, 2, 3 or 4; and    -   is 0, 1, or 2.

As defined above and described herein each X¹ is independently acovalent bond, —CH₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —O—. In some embodiments, X¹ is —NR—.In some embodiments, X¹ is —CF₂—. In some embodiments, X¹ is

In some embodiments, X¹ is —C(O)—. In some embodiments, X¹ is —C(S)—. Insome embodiments, X¹ is

In certain embodiments, X¹ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, X² and X³ are independently—CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X² and X³ are independently —CH₂—. In someembodiments, X² and X³ are independently —C(O)—. In some embodiments, X²and X³ are independently —C(S)—. In some embodiments, X² and X³ areindependently

In certain embodiments, X² and X³ are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, X⁴ is a covalent bond, —CH₂—,—CR₂—, —O—, —NR—, —CF₂—,

—C(O)—, —C(S)—, or

As define above and described herein, Z¹ and Z² are independently acarbon atom or a nitrogen atom.

In some embodiments, Z¹ and Z² are independently a carbon atom. In someembodiments, Z¹ and Z² are independently a carbon atom.

In certain embodiments, Z¹ and Z² are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, Ring A is a fused ring selectedfrom benzo, a 4-6 membered saturated or partially unsaturatedcarbocyclic or heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, Ring A is benzo. In some embodiments, Ring A is afused 4-6 membered saturated or partially unsaturated carbocyclic orheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A is a fused 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Rig A is

In some embodiments, Ring A is

In certain embodiments, Ring A is selected from those shown in thecompounds of Table 1.

As defined above and described herein, L¹ is a covalent bond or a C₁₋₃bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is aC₁₋₃ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein 1-2 methylene units of the chain are independently andoptionally replaced with —O—, —S—, —C(O)—, —C(S)—, —CR₂—, —CRF—, —CF₂—,—NR—, or —S(O)₂—.

In some embodiments, L¹ is —C(O)—.

In certain embodiments, L¹ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R¹ is independently selectedfrom hydrogen, deuterium, R⁴, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,—OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃, or twoR¹ groups are optionally taken together to form an optionallysubstituted 5-8 membered partially unsaturated or aryl fused ring having0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is R⁴. In some embodiments, R¹ ishalogen. In some embodiments, R¹ is —CN. In some embodiments, R¹ is—NO₂. In some embodiments, R¹ is —OR, In some embodiments, R¹ is —SR, Insome embodiments, R¹ is —NR₂. In some embodiments, R¹ is —S(O)₂R. Insome embodiments, R¹ is —S(O)₂NR₂. In some embodiments, R¹ is —S(O)R. Insome embodiments, R¹ is —CF₂R. In some embodiments, R¹ is —CF₃. In someembodiments, R¹ is —CR₂(OR). In some embodiments, R¹ is —CR₂(NR₂). Insome embodiments, R¹ is —C(O)R. In some embodiments, R¹ is —C(O)OR, Insome embodiments, R¹ is —C(O)NR₂. In some embodiments, R¹ is—C(O)N(R)OR, In some embodiments, R¹ is —OC(O)R. In some embodiments, R¹is —OC(O)NR₂. In some embodiments, R¹ is —C(S)NR₂. In some embodiments,R¹ is —N(R)C(O)OR, In some embodiments, R¹ is —N(R)C(O)R. In someembodiments, R¹ is —N(R)C(O)NR₂. In some embodiments, R¹ is —N(R)S(O)₂R.In some embodiments, R¹ is —OP(O)R₂. In some embodiments, R¹ is—OP(O)(OR)₂. In some embodiments, R¹ is —OP(O)(OR)NR₂. In someembodiments, R¹ is —OP(O)(NR₂)₂. In some embodiments, R¹ is —Si(OR)R₂.In some embodiments, R¹ is —SiR₃. In some embodiments, two R¹ groups areoptionally taken together to form an optionally substituted 5-8 memberedpartially unsaturated or aryl fused ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is fluoro. In some embodiments, R¹ is bromo. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is —OH. In someembodiments, R¹ is —NH₂. In some embodiments, R¹ is —NHCH₃. In someembodiments, R¹ is —N(CH₃)₂. In some embodiments, R¹ is —NHCH(CH₃)₂. Insome embodiments, R¹ is —NHSO₂CH₃. In some embodiments, R¹ is —CH₂OH. Insome embodiments, R¹ is —CH₂NH₂. In some embodiments, R¹ is —C(O)NH₂. Insome embodiments, R¹ is —C(O)NHCH₃. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In certain embodiments, each R¹ is independently selected from thoseshown in the compounds of Table 1.

As defined above and described here, each R is independently selectedfrom hydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same carbon or nitrogen are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted C₁₋₆ aliphatic. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is an optionally substituted a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, two R groups onthe same carbon or nitrogen are optionally taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the carbon or nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

As defined above and described herein, R² is selected from

or hydrogen.

In some embodiment R² is

In some embodiments, R² is hydrogen.

In certain embodiments, R² is selected from those shown in the compoundsof Table 1.

As defined above and described herein, Ring B is phenyl, a 4-10 memberedsaturated or partially unsaturated mono- or bicyclic carbocyclic orheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, wherein Ring B is further optionally substituted with 1-2 oxogroups.

In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a4-10 membered saturated or partially unsaturated mono- or bicycliccarbocyclic or heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur In some embodiments, Ring Bis a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, Ring Bis further optionally substituted with 1-2 oxo groups.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In some embodiments Ring B is

In certain embodiments, Ring B is selected from those shown in thecompounds of Table 1.

As defined above and described herein, each R³ is independently selectedfrom hydrogen, deuterium, R⁴, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,—C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)NR₂, —OP(O)(NR₂)₂, and —SiR₃.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is R⁴. In some embodiments, R³ ishalogen. In some embodiments, R³ is —CN. In some embodiments, R³ is—NO₂. In some embodiments, R³ is —OR, In some embodiments, R³ is —SR, Insome embodiments, R³ is —NR₂. In some embodiments, R³ is —S(O)₂R. Insome embodiments, R³ is —S(O)₂NR₂. In some embodiments, R³ is —S(O)R. Insome embodiments, R³ is —CF₂R. In some embodiments, R³ is —CF₃. In someembodiments, R³ is —CR₂(OR). In some embodiments, R³ is —CR₂(NR₂). Insome embodiments, R³ is —C(O)R. In some embodiments, R³ is —C(O)OR, Insome embodiments, R³ is —C(O)NR₂. In some embodiments, R³ is—C(O)N(R)OR, In some embodiments, R³ is —OC(O)R. In some embodiments, R³is —OC(O)NR₂. In some embodiments, R³ is —N(R)C(O)OR, In someembodiments, R³ is —N(R)C(O)R. In some embodiments, R³ is —N(R)C(O)NR₂.In some embodiments, R³ is —N(R)S(O)₂R. In some embodiments, R³ is—OP(O)R₂. In some embodiments, R³ is —OP(O)(OR)₂. In some embodiments,R³ is —OP(O)(OR)NR₂. In some embodiments, R³ is —OP(O)(NR₂)₂. In someembodiments, R³ is —SiR₃.

In certain embodiments, R³ is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R⁴ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁴ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁴ is an optionally substituted phenyl. In someembodiments, R⁴ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁴ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In certain embodiments, R⁴ is selected from those shown in the compoundsof Table 1.

As defined above and described herein,

is a single or double bond.

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

In certain embodiments,

is selected from those shown in the compounds of Table 1.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In certain embodiments, m is selected from those shown in the compoundsof Table 1.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In certain embodiments, n is selected from those shown in the compoundsof Table 1.

As defined above and described herein, o is 0, 1, or 2.

In some embodiments, o is 0. In some embodiments, o is 1. In someembodiments, o is 2.

In certain embodiments, o is selected from those shown in the compoundsof Table 1.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-1:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is imidazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-2:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, and R² is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is imidazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-3:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, and R² is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is oxazolyl, o is 1, X¹ is —CH₂—, X² andX³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-4:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCAand L is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 0, X¹ is a covalent bond,X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-qqq-5:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —O—, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-qqq-6:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —NR—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-7:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is —CF₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-8:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹ is

X² and X³ are —C(O)—, and Z¹ and Z² are carbon atoms as shown, toprovide a compound of formula I-qqq-9:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is pyridyl, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-10:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is pyridyl, o is 1, X¹ is —CH₂—, X² and X³are —C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide acompound of formula I-qqq-11:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I-qqq, wherein Ring A is benzo, o is 1, X¹, X² and X³ are—C(O)—, and Z¹ and Z² are carbon atoms as shown, to provide a compoundof formula I-qqq-12:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, L¹, R¹, R², and m is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1, below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RPN13 binding moiety thereby forming acompound of formula I-rrr:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, and wherein eachof the variables A, Y, and Z is as described and defined in WO2019/165229, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a Ubr1 binding moiety as described inShanmugasundaram, K. et al, J. Bio. Chem. 2019, doi:10.1074/jbc.AC119.010790, the entirety of each of which is hereinincorporated by reference, thereby forming a compound of formula I-sss-1or I-sss-2:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN binding moiety thereby forming acompound of formula I-ttt:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, and wherein eachof the variables R₁, R₂, R₃, R₄, R₅, Q, X, and n is as described anddefined in US 2019/276474, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moietythereby forming a compound of formula I-uuu-1, I-uuu-2, I-uuu-3 orI-uuu-4:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, and wherein eachof the variables Y, A1, and A³ is as described and defined in WO2019/236483, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a KLHDC2 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-vvv-1, I-vvv-2, I-vvv-3, orI-vvv-4:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an AHR E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF16 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www-1:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an RNF4 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www-2:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an RNF114 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www-3:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an RNF114 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www-4:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF15 E3 ubiquitin ligase binding moietythereby forming a compound of formula I-www-5:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is selected from those in Table 1, below.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moietythereby forming a compound of formula I-xxx:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described herein, and wherein:

-   -   X¹ is a bivalent group selected from —O—, —C(O)—, —C(S)—, —CR₂—,        —NR—, —S(O)—, or —SO₂—;    -   X² is an optionally substituted bivalent group selected from        C₁₋₆ saturated or unsaturated alkylene, phenylenyl, a 5-6        membered heteroarylenyl containing 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or a 4-11 membered        saturated or partially unsaturated monocyclic, bicyclic, bridged        bicyclic, or spirocyclic carbocyclylenyl or heterocyclylenyl        with 1-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   R¹ is R⁴, —CR₂R⁴, —OR, —SR, —NR₂, —CR₂, —CR₂OR, —CR₂NR₂,        —CR₂N(R)C(O)R, —CR₂N(R)C(O)NR₂, —OCR₂, —NRC(O)OR, —NRC(O)R,        —NRC(O)NR₂, or —NRSO₂R;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same atom are taken together with their            intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the atom to which they are            attached, independently selected from nitrogen, oxygen, and            sulfur;    -   R² is hydrogen or

-   -   Ring A is a ring selected from phenyl, a 5-6 membered heteroaryl        containing 1-4 heteroatoms independently selected from nitrogen,        oxygen, or sulfur, or a 4 to 9-membered saturated or partially        unsaturated monocyclic, bicyclic, bridged bicyclic, or        spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, wherein        Ring A is optionally further substituted with 1-2 oxo groups;    -   each of R³ is independently hydrogen, deuterium, R⁴, halogen,        —CN, —NO₂, —OR, —SR, —NR₂, —SiR₃, —SO₂R, —SO₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —CR₂N(R)C(O)R,        —CR₂N(R)C(O)NR₂, —OC(O)R, —OC(O)NR₂, —OP(O)R₂, —OP(O)(OR)₂,        —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R,        —N(R)C(O)NR₂, —N(R)SO₂R, —NP(O)R₂, —N(R)P(O)(OR)₂,        —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)SO₂R; or        -   two R³ groups are optionally taken together to form an            optionally substituted 5-7 membered partially unsaturated or            aryl fused ring having 0-2 heteroatoms independently            selected from nitrogen, oxygen, or sulfur;    -   each R⁴ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; and    -   n is 0, 1, 2, 4, or 5.

In certain embodiments, the present invention provides a compound offormula I-xxx, wherein X² is cyclohexyl as shown, to provide a compoundof formula I-xxx-1:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,X¹, R¹, R³, and n is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-xxx, wherein X² is bicyclo[1.1.1]pentane as shown, to providea compound of formula I-xxx-2:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,X², R¹, R, and n is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I-xxx, wherein LBM is VHL E3 ubiquitin ligase binding moiety,thereby providing a compound of one of the following formulae:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA isas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I-xxx, wherein R¹ is

as shown, to provide a compound of formula I-xxx-8:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,X¹, X², R³, and n is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is human kelch-like ECH-associated protein 1(KEAP1) thereby forming a compound of formula I-yyy-1:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1 binding moiety as recited in Lu et al.,Euro. J. Med. Chem., 2018, 146:251-9, thereby forming a compound offormula I-yyy-2:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1-NRF2 binding moiety thereby forming acompound of formula I-yyy-3 or I-yyy-4:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, and wherein eachof the variables R, R₁, R₅, and R₈ is as described and defined in WO2020/018788, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is KEAP1-NRF2 binding moiety as recited in Tonget al., “Targeted Protein Degradation via a Covalent Reversible DegraderBased on Bardoxolone”, ChemRxiv 2020, thereby forming a compound offormula I-yyy-5 or I-yyy-6:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, both singly and incombination.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a cereblon E3 ubiquitin ligase binding moietythereby forming a compound of formula I-zzz:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        SMARCA are as defined above and described in embodiments herein,        wherein:    -   X¹ and X² are independently a covalent bond, —CR₂—, —O—, —CF₂—,

or X¹ and X² are —CR═CR—;

-   -   X³ and X⁴ are independently —CH₂—, —C(O)—, —C(S)—, or

-   -   Ring P and Ring Q are independently fused rings selected from a        5-6 membered saturated, partially unsaturated, or heteroaryl        ring having 0-4 heteroatoms, in addition to the nitrogen already        depicted in Ring X and Ring Y, independently selected from        nitrogen, oxygen, and sulfur;    -   each R^(a) and R^(b) are independently selected from hydrogen,        deuterium, R^(∘), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R,        —S(O)₂NR₂, —S(O)R, —CF₂R, —CF₃, —CR₂(OR), —CR₂(NR₂), —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —C(S)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —OP(O)R₂,        —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and —SiR₃;    -   each R is independently selected from hydrogen, or an optionally        substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7        membered saturated or partially unsaturated heterocyclic having        1-2 heteroatoms independently selected from nitrogen, oxygen,        and sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same carbon or nitrogen are optionally            taken together with their intervening atoms to form an            optionally substituted 4-7 membered saturated, partially            unsaturated, or heteroaryl ring having 0-3 heteroatoms, in            addition to the carbon or nitrogen, independently selected            from nitrogen, oxygen, and sulfur;    -   each R^(c) is independently selected from an optionally        substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7        membered saturated or partially unsaturated heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, and a 5-6 membered heteroaryl ring having        1-4 heteroatoms independently selected from nitrogen, oxygen,        and sulfur;    -   a is 0, 1, 2, 3 or 4; and    -   b is 0, 1, 2, 3 or 4.

As defined above and described herein, X¹ and X² are independently acovalent bond, —CR₂—, —O—, —CF₂—,

or X¹ and X² are —CR═CR—.

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CR₂—. In some embodiments, X¹ is In some embodiments, X¹ is —O—. Insome embodiments, X¹ is —CF₂—. In some embodiments, X¹ is

In some embodiments, X² is a covalent bond. In some embodiments, X² is—CR₂—. In some embodiments, X² is —CH₂—. In some embodiments, X² is —O—.In some embodiments, X² is —CF₂—. In some embodiments, X² is

In some embodiments, X¹ and X² are —CR═CR—. In some embodiments, X¹ andX² are —CH═CH—.

In some embodiments, X¹ and X² are independently selected from thoseshown in the compounds of Table 1.

As defined above and described herein, X³ and X⁴ are independently—CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X³ is —CH₂—. In some emboeiments, X³ is —C(O)—. Insome embodiments, X³ is —C(S)—. In some embodiments, X³ is

In some embodiments, X⁴ is —CH₂—. In some emboeiments, X⁴ is —C(O)—. Insome emboeiments, X⁴ is —C(S)—. In some emboeiments, X⁴ is

In some embodiments, X³ and X⁴ are selected from those shown in thecompounds of Table 1.

As defined above and described herein, Ring X and Ring Y areindependently fused rings selected from a 5-6 membered saturated,partially unsaturated, or heteroaryl ring having 0-4 heteroatoms, inaddition to the nitrogen already depicted in Ring X and Ring Y,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring P and Ring Q are independently fused ringsselected from a 5-6 membered saturated, partially unsaturated, orheteroaryl ring having 0-4 heteroatoms, in addition to the nitrogenalready depicted in Ring P and Ring Q, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring P is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In some embodiments, Ring Q is

In certain embodiments, Ring P and Ring Q are selected from those shownin the compounds of Table 1.

As defined above and described herein, each R^(a) and R^(b) areindependently selected from hydrogen, deuterium, R^(∘), halogen, —CN,—NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃,—CR₂(OR), —CR₂(NR₂), —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —C(S)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,—OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂, —Si(OR)R₂, and—SiR₃.

In some embodiments, R^(a) is hydrogen. In some embodiments, R^(a) isdeuterium. In some embodiments, R^(a) is R^(∘). In some embodiments,R^(a) is halogen. In some embodiments, R^(a) is —CN. In someembodiments, R^(a) is —NO₂. In some embodiments, R^(a) is —OR, In someembodiments, R^(a) is —SR, In some embodiments, R^(a) is —NR₂. In someembodiments, R^(a) is —S(O)₂R. In some embodiments, R^(a) is —S(O)₂NR₂.In some embodiments, R^(a) is —S(O)R. In some embodiments, R^(a) is—CFR₂. In some embodiments, R^(a) is —CF₂R. In some embodiments, R^(a)is —CF₃. In some embodiments, R^(a) is —CR₂(OR). In some embodiments,R^(a) is —CR₂(NR₂). In some embodiments, R^(a) is —C(O)R. In someembodiments, R^(a) is —C(O)OR, In some embodiments, R^(a) is —C(O)NR₂.In some embodiments, R^(a) is —C(O)N(R)OR, In some embodiments, R^(a) is—OC(O)R. In some embodiments, R^(a) is —OC(O)NR₂. In some embodiments,R^(a) is —C(S)NR₂. In some embodiments, R^(a) is —N(R)C(O)OR, In someembodiments, R^(a) is —N(R)C(O)R. In some embodiments, R^(a) is—N(R)C(O)NR₂. In some embodiments, R^(a) is —N(R)S(O)₂R. In someembodiments, R^(a) is —OP(O)R₂. In some embodiments, R^(a) is—OP(O)(OR)₂. In some embodiments, R^(a) is —OP(O)(OR)NR₂. In someembodiments, R^(a) is —OP(O)(NR₂)₂. In some embodiments, R^(a) is—Si(OR)R₂. In some embodiments, R^(a) is —SiR₃.

In some embodiments, R^(b) is hydrogen. In some embodiments, R^(b) isdeuterium. In some embodiments, R^(b) is R^(∘). In some embodiments,R^(b) is halogen. In some embodiments, R^(b) is —CN. In someembodiments, R^(b) is —NO₂. In some embodiments, R^(b) is —OR, In someembodiments, R^(b) is —SR, In some embodiments, R^(b) is —NR₂. In someembodiments, R^(b) is —S(O)₂R. In some embodiments, R^(b) is —S(O)₂NR₂.In some embodiments, R^(b) is —S(O)R. In some embodiments, R^(b) is—CFR₂. In some embodiments, R^(b) is —CF₂R. In some embodiments, R^(b)is —CF₃. In some embodiments, R^(b) is —CR₂(OR). In some embodiments,R^(b) is —CR₂(NR₂). In some embodiments, R^(b) is —C(O)R. In someembodiments, R^(b) is —C(O)OR, In some embodiments, R^(b) is —C(O)NR₂.In some embodiments, R^(b) is —C(O)N(R)OR, In some embodiments, R^(b) is—OC(O)R. In some embodiments, R^(b) is —OC(O)NR₂. In some embodiments,R^(b) is —C(S)NR₂. In some embodiments, R^(b) is —N(R)C(O)OR, In someembodiments, R^(b) is —N(R)C(O)R. In some embodiments, R^(b) is—N(R)C(O)NR₂. In some embodiments, R^(b) is —N(R)S(O)₂R. In someembodiments, R^(b) is —OP(O)R₂. In some embodiments, R^(b) is—OP(O)(OR)₂. In some embodiments, R^(b) is —OP(O)(OR)NR₂. In someembodiments, R^(b) is —OP(O)(NR₂)₂. In some embodiments, R^(b) is—Si(OR)R₂. In some embodiments, R^(b) is —SiR₃.

In certain embodiments, each R^(a) and R^(b) are selected from thoseshown in the compounds of Table 1.

As defined above and described herein, each R is independently selectedfrom hydrogen, or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R groups on the same carbon or nitrogen are optionallytaken together with their intervening atoms to form an optionallysubstituted 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the carbon or nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted C₁₋₆ aliphatic. In some embodiments, R is anoptionally substituted phenyl. In some embodiments, R is an optionallysubstituted 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R is an optionally substituted a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, two R groups onthe same carbon or nitrogen are optionally taken together with theirintervening atoms to form an optionally substituted 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the carbon or nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In certain embodiments, R is selected from those shown in the compoundsof Table 1.

As defined above and described herein, each R^(∘) is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R is an optionally substituted phenyl. In someembodiments, R is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(∘) is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In certain embodiments, R is selected from those shown in the compoundsof Table 1.

As defined above and described herein, a is 0, 1, 2, 3 or 4.

In some embodiments, a is 0. In some embodiments, a is 1. In someembodiments, a is 2. In some embodiments, a is 3. In some embodiments, ais 4.

In certain embodiments, a is selected from those shown in the compoundsof Table 1.

As defined above and described herein, b is 0, 1, 2, 3 or 4.

In some embodiments, b is 0. In some embodiments, b is 1. In someembodiments, b is 2. In some embodiments, b is 3. In some embodiments, bis 4.

In certain embodiments, b is selected from those shown in the compoundsof Table 1.

In some embodiments, the present invention provides a compound offormula I, wherein X¹ and X² are —CH₂—, and X³ and X⁴ are —C(O)— asshown, to provide a compound of formula I-zzz-1:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, Ring P, Ring Q, R^(a), R^(b), a, and b is as defined above anddescribed in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, and Ring Qis

as shown, to provide a compound of formula I-zzz-2:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, Ring P, R^(a), R^(b), a, and b is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, and Ring Pis

as shown, to provide a compound of formula I-zzz-3:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, Ring Q, R^(a), R^(b), a, and b is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I, wherein X¹ and X² are —CH₂—, X³ and X⁴ are —C(O)—, Ring P is

and Ring Q is

as shown, to provide a compound of formula I-zzz-4:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCA,L, R^(a), R^(b), x, and y is as defined above and described inembodiments herein, both singly and in combination.

Lysine Mimetic

In some embodiments, DIM is a lysine mimetic. In some embodiments, thecovalent attachment of ubiquitin to one or more SMARCA2, SMARCA4, or PB1protein is achieved through the action of a lysine mimetic. In someembodiments, upon the binding of a compound of formula I to SMARCA2, themoiety that mimics a lysine undergoes ubiquitination thereby markingSMARCA2 for degradation via the Ubiquitin-Proteasome Pathway (UPP). Insome embodiments, upon the binding of a compound of formula I toSMARCA4, the moiety that mimics a lysine undergoes ubiquitinationthereby marking SMARCA4 for degradation via the Ubiquitin-ProteasomePathway (UPP). In some embodiments, upon the binding of a compound offormula I to PB1, the moiety that mimics a lysine undergoesubiquitination thereby marking PB1 for degradation via theUbiquitin-Proteasome Pathway (UPP).

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is

In some embodiments, DIM is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides the compound offormula I wherein DIM is

thereby forming a compound of formula I-kkk-1:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCAand L is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides the compound offormula I wherein DIM is NH

thereby forming a compound of formula I-kkk-2:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCAand L is as defined above and described in embodiments herein, bothsingly and in combination.

In some embodiments, the present invention provides the compound offormula I wherein DIM is

thereby forming a compound of formula I-kkk-3:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCAand L is as defined above and described in embodiments herein, bothsingly and in combination.

In certain embodiments, the present invention provides a compound ofFormula I, wherein DIM is lysine mimetic

thereby forming a compound of formulae I-111-1, I-111-2, or I-111-3,respectively:

or a pharmaceutically acceptable salt thereof, wherein L and SMARCA areas defined above and described in embodiments herein, and wherein eachof the variables R¹, R⁴, R⁵, A, B, E, Y, Y′, Z, Z′, and k are as definedand described in U.S. Pat. No. 7,622,496, the entirety of each of whichis herein incorporated by reference.

Hydrogen Atom

In some embodiments, DIM is a hydrogen atom. In some embodiments, thecovalent attachment of ubiquitin to one or more SMARCA2, SMARCA4 or PB1proteins is achieved through a provided compound wherein DIM is ahydrogen atom. In some embodiments, upon the binding of a compound offormula I to SMARCA2, the DIM moiety being hydrogen effectuatesubiquitination thereby marking SMARCA2 for degradation via theUbiquitin-Proteasome Pathway (UPP). In some embodiments, upon thebinding of a compound of formula I to SMARCA4, the DIM moiety beinghydrogen effectuates ubiquitination thereby marking SMARCA4 fordegradation via the Ubiquitin-Proteasome Pathway (UPP). In someembodiments, upon the binding of a compound of formula I to PB1, the DIMmoiety being hydrogen effectuates ubiquitination thereby marking PB1 fordegradation via the Ubiquitin-Proteasome Pathway (UPP).

In some embodiments, DIM is selected from those depicted in Table 1,below.

In some embodiments, the present invention provides the compound offormula I wherein DIM is a hydrogen atom, thereby forming a compound offormula I-mmm:

or a pharmaceutically acceptable salt thereof, wherein each of SMARCAand L is as defined above and described in embodiments herein, bothsingly and in combination.

Linker (L)

As defined above and described herein, L is a bivalent moiety thatconnects SMARCA to DIM.

In some embodiments, L is a bivalent moiety that connects SMARCA to LBM.In some embodiments, L is a bivalent moiety that connects SMARCA to alysine mimetic. In some embodiments, L is a bivalent moiety thatconnects SMARCA to a hydrogen atom.

In some embodiments, L¹ is a covalent bond or a bivalent, saturated orpartially unsaturated, straight or branched C₁_so hydrocarbon chain,wherein 0-6 methylene units of L are independently replaced by—C(D)(H)—, —C(D)₂-, —Cy—, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,—P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,—S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)C(O)O—,

wherein each —Cy— is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-11membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-11 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein r is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10, and R is as described herein (e.g., in formula I-a).

In some embodiments, L is a covalent bond. In some embodiments, each—Cy— is independently an optionally substituted bivalent phenylenyl. Insome embodiments, each —Cy— is independently an optionally substituted8-10 membered bicyclic arylenyl. In some embodiments, each —Cy— isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated carbocyclylenyl. In some embodiments, each —Cy— isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated spiro carbocyclylenyl. In some embodiments, each—Cy— is independently an optionally substituted 8-10 membered bicyclicsaturated or partially unsaturated carbocyclylenyl. In some embodiments,each —Cy— is independently an optionally substituted 4-7 memberedsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, each —Cy— is independently an optionally substituted4-7 membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each —Cy— is independently an optionallysubstituted 8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, each —Cy— isindependently an optionally substituted 5-6 membered heteroarylenylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each —Cy— is independently an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is

In some embodiments, —Cy— is selected from those depicted in Table 1,below.

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is selected from those depicted in Table 1,below.

Without limitation, the point of attachment of L to SMARCA and DIM canbe, for example when L is

either

In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, ris 4. In some embodiments, r is 5. In some embodiments, r is 6. In someembodiments, r is 7. In some embodiments, r is 8. In some embodiments, ris 9. In some embodiments, r is 10.

In some embodiments, r is selected from those depicted in Table 1,below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

In some embodiments, a provided compound or pharmaceutically acceptablesalt thereof, is selected from those wherein SMARCA is

LBM is selected from any of those in Table A below, and L is selectedfrom any of those in Table B below.

TABLE A Exemplified E3 ligases (LBM)

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

(i)

(j)

(k)

(l)

(m)

(n)

(o)

(p)

(q)

(r)

(s)

(t)

(u)

(v)

(w)

(x)

(y)

(z)

(aa)

(bb)

(cc)

(dd)

(ee)

(ff)

(gg)

(hh)

(ii)

(jj)

(kk)

(ll)

(mm)

(nn)

(oo)

(pp)

(qq)

(rr)

(ss)

(tt)

(uu)

(vv)

(ww)

(xx)

(yy)

(zz)

(aaa)

(bbb)

(ccc)

(ddd)

(eee)

(fff)

(ggg)

(hhh)

(iii)

(jjj)

(kkk)

(lll)

(mmm)

(nnn)

(ooo)

(ppp)

(qqq)

(rrr)

(sss)

(ttt)

(uuu)

(vvv)

(www)

(xxx)

(yyy)

(zzz)

(aaaa)

(bbbb)

(cccc)

(dddd)

(eeee)

TABLE B Exemplified Linkers (L)

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

(236)

(237)

(238)

(239)

(240)

(241)

(242)

(243)

(244)

(245)

(246)

(247)

(248)

(249)

(250)

(251)

(253)

(254)

(255)

(256)

(257)

(258)

(259)

(260)

(261)

(262)

(263)

(264)

(265)

(266)

(267)

(268)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(345)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)

(435)

(436)

(437)

(438)

(438)

(439)

(440)

(441)

(442)

(443)

(444)

(445)

(446)

(447)

(448)

(449)

(450)

(451)

(452)

(453)

(454)

(455)

(456)

(457)

(458)

(459)

(460)

(461)

(462)

(463)

(464)

(465)

(466)

(467)

(468)

(469)

(470)

(471)

(472)

(473)

(474)

(475)

(475)

(476)

(477)

(478)

(479)

(480)

(481)

(482)

(483)

(484)

(485)

(486)

(487)

(488)

(489)

(490)

(491)

(492)

(493)

(494)

(495)

(496)

(497)

(498)

(499)

(500)

(501)

(502)

(503)

(504)

(505)

(506)

(507)

(508)

(509)

(510)

(511)

(512)

(513)

(514)

(515)

(516)

(517)

(518)

(519)

(520)

(521)

(522)

(523)

(524)

(525)

(526)

(527)

(528)

(529)

(530)

(531)

(532)

(533)

(534)

(535)

(536)

(537)

(538)

(539)

(540)

(541)

(542)

(543)

(544)

(545)

(546)

(547)

(548)

(549)

(550)

(551)

(552)

(553)

(554)

(555)

(556)

(557)

(558)

(559)

(560)

(561)

(562)

(563)

(564)

(565)

(566)

(567)

(568)

(569)

(570)

(571)

(572)

(573)

(574)

(575)

(576)

(577)

(578)

(579)

(580)

(581)

(582)

(583)

(584)

(585)

(586)

(587)

(588)

(589)

(590)

(591)

(592)

(593)

(594)

(595)

(596)

(597)

(598)

(599)

(600)

(601)

(602)

(603)

(604)

(605)

(606)

(607)

(608)

(609)

(610)

(611)

(612)

(613)

(614)

(615)

(616)

(617)

(618)

(619)

(620)

(621)

(622)

(623)

(624)

(625)

(626)

(627)

(628)

(629)

(630)

(631)

(632)

(633)

(634)

(635)

(636)

(637)

(638)

(639)

(640)

(641)

(642)

In some embodiments, the present invention provides a compound having anSMARCA binding moiety described and disclosed herein, a LBM set forth inTable A above, and a linker set forth in Table B above, or apharmaceutically acceptable salt thereof.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group, leavinggroup, or transformation condition is depicted, one of ordinary skill inthe art will appreciate that other protecting groups, leaving groups,and transformation conditions are also suitable and are contemplated.Such groups and transformations are described in detail in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.Smith and J. March, 5^(th) Edition, John Wiley & Sons, 2001,Comprehensive Organic Transformations, R. C. Larock, 2^(nd) Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,the entirety of each of which is hereby incorporated herein byreference.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Examplesof suitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of each of which is herein incorporated by reference. Suitableamino protecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In the schemes below, where a final degrader is formed having a reactiveDIM moiety (e.g., amine, alcohol, etc.), it is not shown but it isgenerally appreciated and well known by those having ordinary skill inthe art that the reactivity of said reactive DIM moiety may be masked byemploying a suitable protecting group that can thereafter be removed insitu or during a separate synthetic step to form the final degraderproduct.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 1 set forth below:

As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between SMARCA and the terminalamino group of A-1 or the portion of the linker between DIM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP—Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 2 set forth below:

As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between SMARCA and the terminalamino group of A-1 or the portion of the linker between DIM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP—Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 3 set forth below:

As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of the invention with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between SMARCA and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP—Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 4 set forth below:

As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising an amide bond.The squiggly bond,

, represents the portion of the linker between SMARCA and the terminalcarboxyl group of A-3 or the portion of the linker between DIM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP—Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 5 set forth below:

As depicted in Scheme 5, above, an S_(N)Ar displacement of fluoride A-6by amine A-5 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between SMARCA and the terminalamino group of A-5.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 6 set forth below:

As depicted in Scheme 6, above, an S_(N)Ar displacement of fluoride A-7by amine A-8 is effected in the presence of the base DIPEA in DMF toform a compound of the invention with a linker comprising a secondaryamine. The squiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-8.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 7 set forth below:

As depicted in Scheme 7, above, reductive alkylation of aldehyde A-9 byamine A-10 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between DIM and the terminalamino group of A-10.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 8 set forth below:

As depicted in Scheme 8, above, reductive alkylation of aldehyde A-12 byamine A-11 is effected in the presence of a mild hydride source (e.g.,sodium cyanoborohydride or sodium triacetoxyborohydride) to form aprovided compound with a linker comprising a secondary amine. Thesquiggly bond,

, represents the portion of the linker between SMARCA and the terminalamino group of A-11.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. See for example, “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entirety of each of which isherein incorporated by reference. Such interconversions may require oneor more of the aforementioned techniques, and certain methods forsynthesizing compounds of the invention are described below in theExemplification.

5. Uses, Formulation and Administration

Pharmaceutically acceptable compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably degrade and/or inhibit a SMARCAand/or PB1 protein, or a mutant thereof, in a biological sample or in apatient. In certain embodiments, the amount of compound in compositionsof this invention is such that is effective to measurably degrade and/orinhibit a SMARCA and/or PB1 protein, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition. In some embodiments, a composition of thisinvention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily or degratorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof a SMARCA and/or PB1 protein, or a mutant thereof.

As used herein, the term “degratorily active metabolite or residuethereof” means that a metabolite or residue thereof is also a degraderof an SMARCA and/or PB1 protein, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for thedegradation and/or inhibition of a SMARCA or PB1 protein activity.

Examples of SMARCA proteins that are degraded and/or inhibited by thecompounds and compositions described herein and against which themethods described herein are useful include those of the SWI/SNF-relatedmatrix-associated actin-dependent regulators of chromatin subfamily A(“SMARCA”) family of proteins, the members of which include SMARCA1,SMARCA2, SMARCA4, or SMARCA5, or a mutant thereof. See e.g., Shain andPollack “The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers.PLoS One 2013, 8:e55119; Kadoch and Crabtree “Mammalian SWI/SNFChromatin Remodeling Complexes and Cancer: Mechanistic Insights Gainedfrom Human Genomics” Sci. Adv. 2015, 1:e1500447; Wilson and Roberts“SWI/SNF Nucleosome Remodelers and Cancer” Nat. Rev. Cancer 2011,11:481; and Son and Crabtree “The Role of BAF (mSWI/SNF) Complexes inMammalian Neural Development” Am. J Med. Genet., Part C 2014, 166:333,the entirety of each of which is herein incorporated by reference.

The activity of a compound utilized in this invention as a degraderand/or inhibitor of one or more SMARCA or PB1, or a mutant thereof, maybe assayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the activity and/or thesubsequent functional consequences of activated SMARCA or PB1 protein,or a mutant thereof. Alternate in vitro assays quantitate the ability ofthe inhibitor to bind to a SMARCA or PB1 protein. Inhibitor binding maybe measured by radiolabeling the inhibitor prior to binding, isolatingthe inhibitor/SMARCA or PB1 complex and determining the amount ofradiolabel bound. Alternatively, inhibitor binding may be determined byrunning a competition experiment where new inhibitors are incubated witha SMARCA or PB1 protein bound to known radioligands. Representative invitro and in vivo assays useful in assaying a SMARCA or PB1 inhibitorinclude those described and disclosed in, e.g., Tanaka et al. “Designand Characterization of Bivalent BET Inhibitors” Nat. Chem. Biol. 2016,12(12):1089; Schiaffino-Ortega et al. “SWI/SNF as targets in cancertherapy” J. Hematol. Oncol. 2014, 7:81; Filippakopoulos et al. “HistoneRecognition and Large-Scale Structural Analysis of the Human BromodomainFamily” Cell 2012, 149:214. Detailed conditions for assaying a compoundutilized in this invention as a degrader and/or inhibitor of a SMARCA orPB1 protein, or a mutant thereof, are set forth in the Examples below.

Chromatin is a complex combination of DNA and protein that makes upchromosomes. Chromatin functions to package, strengthen, and controlexpression and DNA replication. The chromatin structure is controlled bya series of post-translational modifications, most commonly within the“histone tails” which extend beyond the core nucleosome structure. Theseepigenetic modifications including acetylation, methylation,phosphorylation, ubiquitinylation, and SUMOylation, is then interpretedby the cell to allow gene specific regulation of chromatin structure andthereby transcription. Histone modifications are dynamic, as they can beadded or removed in response to specific stimuli, and thesemodifications direct both structural changes to chromatin andalterations in gene transcription. Distinct classes of enzymes, namelyhistone acetyltransferases (HATs) and histone deacetylases (HDACs),acetylate or de-acetylate specific histone lysine residues (Struhl,Genes Dev. 1989, 12(5):599).

Bromodomains, which are approximately 110 amino acids long, are found ina large number of chromatin-associated proteins and have been identifiedin approximately 70 human proteins, often adjacent to other proteinmotifs (Jeanmougin et al., Trends Biochem. Sci. 1997, 22(5):151; Tamkunet al., Cell 1992, 7(3):561). Interactions between bromodomains andmodified histones may be an important mechanism underlying chromatinstructural changes and gene regulation. Bromodomain-containing proteinshave been implicated in disease processes including cancer, inflammationand viral replication. See, e.g., Prinjha et al, Trends Pharm. Sci.2012, 33(3):146; Muller et al. Expert Rev. 2011, 13(29):1.

Cell-type specificity and proper tissue functionality requires the tightcontrol of distinct transcriptional programs that are intimatelyinfluenced by their environment. Alterations to this transcriptionalhomeostasis are directly associated with numerous disease states, mostnotably cancer, immuno-inflammation, neurological disorders, andmetabolic diseases. Bromodomains reside within key chromatin modifyingcomplexes that serve to control distinctive disease-associatedtranscriptional pathways. An example of such a complex is theswitch/sucrose nonfermenting (“SWI/SNF”) chromatin-remodeling complex,which has been reported to be involved in gene regulation, cell lineagespecification and development, and comprises a number of bromodomaincontaining subunits, including SWI/SNF-related matrix-associatedactin-dependent regulator of chromatin subfamily A member 2 and 4(SMARCA2 and SMARCA4) and polybromo-1 (PB1; also known as PBRM1).SMARCA2 and SMARCA4, also known as transcription activators Brahmahomologue (BRM) and Brahma-related gene 1 (BRG1) respectively, aremutually exclusive helicase/ATPase proteins of the large ATP-dependentSWI/SNF chromatin-remodeling complexes involved in transcriptionalregulation of gene expression. In some embodiments, a provided compoundbinds to one or more SMARCA2, SMARCA4, or PB1 bromodomains. In someembodiments, a provided compound binds to one or more SMARCA2, SMARCA4,or PB1 ATPase domains.

Representative SMARCA2, SMARCA4, and/or PB1 inhibitors include thosedescribed and disclosed in e.g., Gerstenberger et al. J. Med. Chem.2016, 59(10):4800; Theodoulou et al. Curr Opin. Chem. Bio. 2016, 33:58;Vangamudi et al. Cancer Res. 2015, 75(18):3865; the entirety of each ofwhich is herein incorporated by reference.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are degraders and/or inhibitors of one of moreSMARCA2, SMARCA4, or PB1 protein and are therefore useful for treatingone or more disorders associated with activity of one or more ofSMARCA2, SMARCA4, or PB1 protein. Thus, in certain embodiments, thepresent invention provides a method for treating a SMARCA2-mediated,SMARCA4-mediated, or PB1-mediated disorder comprising the step ofadministering to a patient in need thereof a compound of the presentinvention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “SMARCA2-mediated”, “SMARCA4-mediated”, or“PB1-mediated” disorders, diseases, and/or conditions as used hereinmeans any disease or other deleterious condition in which one or moreSMARCA2, SMARCA4, or PB1, or a mutant thereof, are known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in which oneor more SMARCA2, SMARCA4, or PB1, or a mutant thereof, are known to playa role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is a cancer, a neurodegenative disorder,a viral disease, an autoimmune disease, an inflammatory disorder, ahereditary disorder, a hormone-related disease, a metabolic disorder,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, or aCNS disorder.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer (see, e.g.,Schiaffino-Ortega et al. J. Hematol. Oncol. 2014, 7:81; Medina et al.Gene Chromosome Canc. 2014, 41:170), diabetes, cardiovascular disease(see, e.g., Bevilacqua et al., Cardiovasc. Pathol. 2013, 23(2):85),viral disease, autoimmune diseases such as lupus, and rheumatoidarthritis, autoinflammatory syndromes, atherosclerosis (see, e.g.,Ortiz-Mao et al., J. Proteom Genom Res. 2017, 2(1):1), psoriasis,allergic disorders, inflammatory bowel disease, inflammation, acute andchronic gout and gouty arthritis, neurological disorders (see, e.g.,Pandey et al., J. Hum. Genet. 2004, 49:596), metabolic syndrome,immunodeficiency disorders such as AIDS and HIV (see, e.g., Boehm etal., Viruses 2013, 5:1571), genetic disorders (see, e.g., Kosho et al.,Am. J. Med. Genet. 2014, 166(3):262; Tang et al., Am. J. Med. Genet.2015, 173(1):195), destructive bone disorders, osteoarthritis (see,e.g., Tian, J Orthop. Surg. Res. 2018, 13:49), proliferative disorders(see, e.g., Cruickshank et al., PLoS One 2015, 10(11):e0142806),Waldenström's Macroglobulinemia. infectious diseases, conditionsassociated with cell death, pathologic immune conditions involving Tcell activation, and CNS disorders (see, e.g., Koga et al., Human Mol.Gen. 2009, 18(13):2483) in a patient. In one embodiment, a human patientis treated with a compound of the current invention and apharmaceutically acceptable carrier, adjuvant, or vehicle, wherein saidcompound is present in an amount to measurably degrade and/or inhibitone or more SMARCA2, SMARCA4, or PB1, or a mutant thereof

Compounds of the current invention are useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder,breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMyD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma).

In certain embodiments, the cancer treated by a provided compound islung cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer,glioma, breast cancer, pancreatic cancer, colorectal cancer, bladdercancer, endometrial cancer, penile cancer, esophagogastric cancer,hepatobiliary cancer soft tissue sarcoma, ovarian cancer, head and neckcancer, renal cell carsinoma, bone cancer, non-Hodgkin lymphoma,prostate cancer, embryonal tumors, germ cell tumors, cervical cancer,thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrinetumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer,thymic tumor, adrenocortical carcinoma, appendiceal cancer, small bowelcancer, non-melanoma skin cancer, and/or melanoma. In some embodiments,the cancer is lung cancer. In some embodiments, the lung cancer isNSCLC. In some embodiments, the cancer is breast cancer. In someembodiments, the cancer is melanoma.

In some embodiments, the present invention provides a method of treatinglung cancer in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingnon-small cell lung cancer (NSCLC) in a patient in need thereof,comprising administering a compound of the present invention, or apharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method of treatingglioma in a patient in need thereof, comprising administering a compoundof the present invention, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method of treatingbreast cancer in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingpancreatic cancer in a patient in need thereof, comprising administeringa compound of the present invention, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the present invention provides a method of treatingcolorectal cancer in a patient in need thereof, comprising administeringa compound of the present invention, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the present invention provides a method of treatingbladder cancer in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingendometrial cancer in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingpenile cancer in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingnon-melanoma skin cancer in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present invention provides a method of treatingmelanoma in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

SMARCA2 has recently been reported as a synthetic lethal target inSMARCA4-deficient cancers (e.g., cancers comprising SMARCA4 loss offunction mutations and/or cancers having reduced or absent expression,e.g., due to epigenetic alterations). SMARCA2 depletion has been shownto selectively inhibit the growth of SMARCA4-mutant cancer cells(Hoffman et al., PNAS 2014, 111(8):3128; Oike et al., Cancer Res. 2013,73(17):5508). In some embodiments, the cancer treated by aprovidedcompound is a SMARCA4-deficient cancer (e.g, a cancer harboring a lossof function mutation and/or having reduced or absent SMARCA4expression).

It has also been shown that certain cancers are dependent on SMARCA4 fordisease progression and are vulnerable to SMARCA4 inhibition, includingcertain acute leukemia and small cell lung cancers (Hohmann et al.,Trends in Genetics, 2014, 30(8):356). In some embodiments, the cancertreated by a provided compound is leukemia (e.g., acute leukemia, e.g.,acute myleloid leukemia), breast cancer, small cell lung cancer, ormalignant rhabdoid tumors (MRT) (e.g., a SNF5-deficient malignantrhabdoid tumor).

In some embodiments, the present invention provides a method of treatingleukemia in a patient in need thereof, comprising administering acompound of the present invention, or a pharmaceutically acceptable saltthereof.

In some embodiments, the present invention provides a method of treatingmalignant rhabdoid tumors (MRT) in a patient in need thereof, comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

Compounds according to the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample anti-inflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”: “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterized by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiform is, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitits, atompic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiform is, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, and other inflammatory or allergic conditions of theskin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from Systemiclupus erythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke,congestive heart failure, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, and deep venous thrombosis.

In some embodiments, the neurodegenerative disease which can be treatedaccording to the methods of this invention include, but are not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolicsyndrome, obesity, organ transplantation and graft versus host disease.

In some embodiments the invention provides a method of treating,preventing or lessening the severity of Alzheimer's disease comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt or composition thereof.

In some embodiments the invention provides a method of treating adisease or condition commonly occurring in connection withtransplantation. In some embodiments, the disease or condition commonlyoccurring in connection with transplantation is selected from organtransplantation, organ transplant rejection, and graft versus hostdisease.

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

In some embodiments the invention provides a method of treating a viraldisease. In some embodiments, the viral infection is HIV infection.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of a proliferative disease, an inflammatory disease, anobstructive respiratory disease, a cardiovascular disease, a metabolicdisease, a neurological disease, a neurodegenerative disease, a viraldisease, or a disorder commonly occurring in connection withtransplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif*), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents may be partof a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours apart.

In one embodiment, the present invention provides a compositioncomprising a provided compound and one or more additional therapeuticagents. The therapeutic agent may be administered together with aprovided compound, or may be administered prior to or followingadministration of a provided compound. Suitable therapeutic agents aredescribed in further detail below. In certain embodiments, a providedcompound may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. Inother embodiments, a provided compound may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursfollowing the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine(Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound and one or more additional therapeuticagents selected from non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarialssuch as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®),methotrexate (Rheumatrex®), gold salts such as gold thioglucose(Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®),D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®),cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine(Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such asetanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®),certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1”agents such as anakinra (Kineret®) and rilonacept (Arcalyst®),antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such asabatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab(Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound and one or more additional therapeutic agents selectedfrom acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) suchas aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) andmonoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot® and anticholinergics or antispasmodics such as dicyclomine(Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagylor ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a providedcompound and one or more additional therapeutic agents selected fromnucleoside reverse transcriptase inhibitors such as zidovudine(Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from rituximab (Rituxan®), cyclophosphamide(Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a provided compound and one or more additionaltherapeutic agents selected from chlorambucil (Leukeran®),cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine(Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor —beta (TGF-beta or TGFβ). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGFβtrap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFβ“trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF 1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a provided compound and one or more additional therapeuticagents selected from donepezil (Aricept®), rivastigmine (Excelon®),galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TK1258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a provided compound and oneor more additional therapeutic agents selected from a steroid,cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTKinhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a BTK inhibitor,wherein the disease is selected from inflammatory bowel disease,arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathicthrombocytopenic purpura (ITP), rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis,diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiplesclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barresyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipidantibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmunegastritis, pernicious anemia, celiac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behcet's disease,chronic fatigue, dysautonomia, membranous glomerulonephropathy,endometriosis, interstitial cystitis, pemphigus vulgaris, bullouspemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferativedisease, rejection of transplanted organs or tissues, AcquiredImmunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes,graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma,allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferativedisorder, e.g., diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acutelymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma,multiple myeloma (also known as plasma cell myeloma), non-Hodgkin'slymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone Bcell lymphoma, nodal marginal zone B cell lymphoma, mantle celllymphoma, mediastinal (thymic) large B cell lymphoma, intravascularlarge B cell lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer,prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mastcell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer,colorectal cancer, pancreatic cancer, diseases of the bone and jointsincluding, without limitation, rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome,systemic sclerosis, osteoporosis, bone cancer, bone metastasis, athromboembolic disorder, (e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, deep venous thrombosis), inflammatory pelvicdisease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis,meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis,gastritis, enteritis, dermatitis, gingivitis, appendicitis,pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy,Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren'sdisease, tissue graft rejection, hyperacute rejection of transplantedorgans, asthma, allergic rhinitis, chronic obstructive pulmonary disease(COPD), autoimmune polyglandular disease (also known as autoimmunepolyglandular syndrome), autoimmune alopecia, pernicious anemia,glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma,vasculitis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson'sdisease, Alzheimer's disease, diabetes, septic shock, systemic lupuserythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenilearthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Waldenström macroglobulinemia, myasthenia gravis, Hashimoto'sthyroiditis, atopic dermatitis, degenerative joint disease, vitiligo,autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease,scleraderma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from a cancer, a neurodegenativedisorder, an angiogenic disorder, a viral disease, an autoimmunedisease, an inflammatory disorder, a hormone-related disease, conditionsassociated with organ transplantation, immunodeficiency disorders, adestructive bone disorder, a proliferative disorder, an infectiousdisease, a condition associated with cell death, thrombin-inducedplatelet aggregation, chronic myelogenous leukemia (CML), chroniclymphocytic leukemia (CLL), liver disease, pathologic immune conditionsinvolving T cell activation, a cardiovascular disorder, and a CNSdisorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound and a PI3K inhibitor,wherein the disease is selected from benign or malignant tumor,carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiform is, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms fortopical ortransdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting SWI/SNF chromatin-remodeling complex activity or degrading aSWI/SNF chromatin-remodeling complex in a biological sample comprisingthe step of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting or degrading SMARCA2, SMARCA4, or PB1, or a mutant thereof,activity in a biological sample comprising the step of contacting saidbiological sample with a compound of this invention, or a compositioncomprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition and/or degradation of a SMARCA or PB1 protein, or a proteinselected from SMARCA2, SMARCA4, or PB1, or a mutant thereof, activity ina biological sample is useful for a variety of purposes that are knownto one of skill in the art. Examples of such purposes include, but arenot limited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

Another embodiment of the present invention relates to a method ofdegrading a protein kinase and/or inhibiting protein kinase activity ina patient comprising the step of administering to said patient acompound of the present invention, or a composition comprising saidcompound.

According to another embodiment, the invention relates to a method ofdegrading and/or inhibiting one or more SMARCA2, SMARCA4, or PB1, or amutant thereof, activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound. In other embodiments, the presentinvention provides a method for treating a disorder mediated by one ormore SMARCA2, SMARCA4, or PB1, or a mutant thereof, in a patient in needthereof, comprising the step of administering to said patient a compoundaccording to the present invention or pharmaceutically acceptablecomposition thereof. Such disorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™. Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™ Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™) The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™ Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof, see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor—receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor—receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporne derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; 1 s is 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aPI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C₁₋₁₀₃₃, EKB-569, GW-2016, ELI,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777 (Zamestra™).The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, such as telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™),); carfilzomib(Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan©), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vemalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approved for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin αlβ2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L¹, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIRI, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MED14736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS.F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WOI1/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor—reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1h68/GLV-1hl53, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor—deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor—related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Jerry L. Adams et al., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiment, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams et al. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. Adamset al.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor—associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor—infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor—associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺(αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MED14736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgGI anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgGI Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MED19447 (Medimmune), an anti-CD73 antibody, insolidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION Abbreviations

-   -   Ac: acetyl    -   AcOH: acetic acid    -   ACN: acetonitrile    -   Ad: adamantly    -   AIBN: 2,2′-azo bisisobutyronitrile    -   Anhyd: anhydrous    -   Aq: aqueous    -   B₂Pin₂: bis        (pinacolato)diboron-4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BH₃: Borane    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   Boc₂O: di-tert-butyl dicarbonate    -   BPO: benzoyl peroxide    -   ^(n)BuOH: n-butanol    -   CDI: carbonyldiimidazole    -   COD: cyclooctadiene    -   d: days    -   DABCO: 1,4-diazobicyclo[2.2.2]octane    -   DAST: diethylaminosulfur trifluoride    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DHP: dihydropyran    -   DIBAL-H: diisobutylaluminum hydride    -   DIPA: diisopropylamine    -   DIPEA or DIEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DME: 1,2-dimethoxyethane    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMP: Dess-Martin periodinane    -   DMSO-dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   ee: enantiomeric excess    -   ESI: electrospray ionization    -   EA: ethyl acetate    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   FA: formic acid    -   h or hrs: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   HCl: hydrochloric acid    -   HPLC: high performance liquid chromatography    -   HOAc: acetic acid    -   IBX: 2-iodoxybenzoic acid    -   IPA: isopropyl alcohol    -   KHMDS: potassium hexamethyldisilazide    -   K₂CO₃: potassium carbonate    -   LAH: lithium aluminum hydride    -   LDA: lithium diisopropylamide    -   m-CPBA: meta-chloroperbenzoic acid    -   M: molar    -   MeCN: acetonitrile    -   MeOH: methanol    -   Me₂S: dimethyl sulfide    -   MeONa: sodium methylate    -   MeI: iodomethane    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MPa: mega pascal    -   MOMCl: methyl chloromethyl ether    -   MsCl: methanesulfonyl chloride    -   MTBE: methyl tert-butyl ether    -   nBuLi: n-butyllithium    -   NaNO₂: sodium nitrite    -   NaOH: sodium hydroxide    -   Na₂SO₄: sodium sulfate    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NFSI: N-Fluorobenzenesulfonimide    -   NMO: N-mrethylnorphohine N-oxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   Pd/C: Palladium on Carbon    -   Pd(OAc)₂: Palladium Acetate    -   PBS: phosphate buffered saline    -   PE: petroleum ether    -   POCl₃: phosphorus oxychloride    -   PPh₃: triphenylphosphine    -   PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   Rel: relative    -   R.T. or rt: room temperature    -   sat: saturated    -   SEMCl: chloromethyl-2-trimethylsilylethyl ether    -   SFC: supercritical fluid chromatography    -   SOCl₂: sulfur dichloride    -   tBuOK: potassium tert-butoxide    -   TBAB: tetrabutylammonium bromide    -   TBAI: tetrabutylammonium iodide    -   TEA: triethylamine    -   Tf: trifluoromethanesulfonate    -   TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride    -   TFA: trifluoroacetic acid    -   TIPS: triisopropylsilyl    -   THF: tetrahydrofuran    -   THP: tetrahydropyran    -   TLC: thin layer chromatography    -   TMEDA: tetramethylethylenediamine    -   pTSA: para-toluenesulfonic acid    -   wt: weight    -   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated.

Proton NMR (H NMR) was conducted in deuterated solvent. In certaincompounds disclosed herein, one or more ¹H shifts overlap with residualproteo solvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 2 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical cSFC AgilentTechnologies 1290 Infinity Prep-cSFC Waters SFC Prep 80

For acidic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with ChromolithFlash RP-18e 25*2.0 mm, eluting with 0.0375 vol % TFA in water (solventA) and 0.01875 vol % TFA in acetonitrile (solvent B). Other LCMS wasrecorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Columnflow was 0.55 ml/min and mobile phases used are (A) 2 mM AmmoniumAcetate in 0.1% Formic Acid in Water and (B) 0.1% Formic Acid inAcetonitrile.

For basic LCMS data: LCMS was recorded on an Agilent 1200 Series LC/MSDor Shimadzu LCMS 2020 equipped with electro-spray ionization andquadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18,2.1×50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C182.1×30 mm columns packed with 5 mm C18-coated silica, eluting with 0.05vol % NH₃·H₂O in water (solvent A) and acetonitrile (solvent B).

HPLC Analytical Method: HPLC was carried out on X Bridge C18 150*4.6 mm,5 micron. Column flow was 1.0 ml/min and mobile phase used are (A) 0.1%Ammonia in water and (B) 0.1% Ammonia in Acetonitrile.

Prep HPLC Analytical Method: The compound was purified on ShimadzuLC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm,5μ. Column flow was 16.0 ml/min. Mobile phases used are (A) 0.1% FormicAcid in Water and (B) Acetonitrile Basic method used (A) 5 mM ammoniumbicarbonate and 0.1% NH3 in Water and (B) Acetonitrile or (A) 0.1%Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra arerecorded at 202 nm & 254 nm.

NMR Method: The 1H NMR spectra were recorded on a Bruker Ultra ShieldAdvance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1.(2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(I-13)

-   -   Step 1: tert-butyl        4-(2-chloropyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate.        To a solution of tert-butyl        4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate        (12.5 g, 40.2 mmol) and 2,4-dichloropyrimidine (5 g, 33.6 mmol)        in 1,4-dioxane (100 mL) was added Pd(dppf)Cl₂ (2.46 g, 3.36        mmol) and sodium carbonate (8.54 g, 80.6 mmol) in H₂O (20 mL).        The mixture was stirred at 80° C. for 12 hours. On the        completion, the reaction mixture was partitioned between H₂O (20        mL) and Ethyl acetate (20 mL*3). The organic phase was        separated, washed with brine (30 mL) and dried over Na₂SO₄,        filtered and concentrated under reduced pressure to give a        residue. Then the residue was purified by column chromatography        (SiO₂, Petroleum ether/Ethyl acetate=I/O to 5/1) to get the        title compound (7 g, 66.3% yield, 94% purity) as a yellow solid.        LC-MS (ESI, m/z): [M-55]+=239.9    -   Step 2: tert-butyl        4-(2-chloropyrimidin-4-yl)piperidine-1-carboxylate. To a        solution of tert-butyl        4-(2-chloropyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate        (2 g, 6.76 mmol) in THF (60 mL) was added PtO₂ (1.54 g, 6.76        mmol) under N₂. The suspension was degassed under vacuum and        purged with H₂ three times. The mixture was stirred under H₂ (15        psi) at 25° C. for 12 hours. On the completion, the reaction        mixture was filtered and concentrated under reduced pressure to        give a residue, then the residue was purified by column        chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 3/1)        to get the title compound (1.5 g, 73.6% yield, 98.8% purity) as        a colorless oil. LC-MS (ESI, m/z): [M-55]*=242.2.    -   Step 3: tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidine-1-carboxylate.        To a solution of tert-butyl        4-(2-chloropyrimidin-4-yl)piperidine-1-carboxylate (459 mg, 1.54        mmol) in DMSO (8 mL) was added DIEA (996 mg, 7.71 mmol, 1.34 mL)        and        3-(2-(methoxymethoxy)phenyl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]        pyrrolo[2,3-c]pyridazine (500 mg, 1.54 mmol). The mixture was        stirred at 100° C. for 12 hours. On completion, the mixture was        filtered by disposable needle filter. Then the mixture was        purified by reversed-phase HPLC (0.1% FA condition) to get the        title compound (500 mg, 49.1% yield, 88.6% purity) as a white        solid. LC-MS (ESI, m/z): [M+1]+=586.3    -   Step 4: (R)-tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidine-1-carboxylate        (6-P1) and (S)-tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidine-1-carboxylate        (6-P2). The isomer was separated by SFC (column: DAICEL        CHIRALPAK IC (250 mm*30 mm,10 um); mobile phase: [0.1% NH₃H₂O        MEOH]; B %: 60%-60%, 4; 90 min) to give compounds: 6-P1 (220 mg,        SFC retention time=1.483 min) as a yellow solid; 6-P2 (230 mg,        SFC retention time=2.283 min).    -   Step 5:        (R)-2-(5-methyl-6-(4-(piperidin-4-yl)pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol.        To a solution of (R)-tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidine-1-carboxylate        (220 mg, 406 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 765        uL). The mixture was stirred at 25° C. for 0.5 hour. On the        completion, the reaction mixture was concentrated under reduced        pressure to give a crude compound (260 mg, crude) used for the        next step directly. Then the 50 mg of crude product was purified        by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile        phase: [water (0.05% HCl)-ACN]; B %: 3%-33%, 11 min) to give the        title compound (30.3 mg, 99.5% purity) as a yellow solid. ¹H NMR        (400 MHz, DMSO-d₆) δ =14.10-13.27 (m, 1H), 9.18-8.86 (m, 2H),        8.72 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.72 (d, J=6.8 Hz, 1H),        7.55-7.41 (m, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.10-7.01 (m, 1H),        6.62 (d, J=5.0 Hz, 1H), 6.15 (d, J=6.4 Hz, 1H), 5.14 (br d,        J=12.8 Hz, 1H), 3.48-3.41 (m, 1H), 3.34 (d, J=12.0 Hz, 2H), 3.11        (br d, J=3.6 Hz, 2H), 2.99 d, J=9.8 Hz, 2H), 2.88 (d, J=4.5 Hz,        1H), 2.07-1.92 (m, 4H), 1.55 (d, J=6.4 Hz, 3H). LC-MS (ESI,        m/z): [M+1]⁺=442.3.    -   Step 6: (R)-methyl        6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]        heptane-2-carboxylate. To a solution of        (R)-2-(5-methyl-6-(4-(piperidin-4-yl)pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol        (138 mg, 311 umol) in THF (2 mL) was added KOAc (91.7 mg, 934        umol), methyl 2-oxospiro[3.3]heptane-6-carboxylate (62.9 mg, 374        umol), NaBH(OAc)₃ (165 mg, 778 umol) and HOAc (56.1 mg, 934        umol). The mixture was stirred at 25° C. for 12 hours. On the        completion, the mixture was filtered by disposable needle        filter, then the mixture was purified by reversed-phase HPLC        (0.1% FA condition) to get the title compound (150 mg, 76.2%        yield, 93.9% purity) as a white solid. LC-MS (ESI, m/z):        [M+1]⁺=594.2    -   Step 7:        (R)-6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]        heptane-2-carboxylic acid. To a solution of (R)-methyl        6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]        heptane-2-carboxylate (150 mg, 253 umol) in THF (3 mL) was added        LiOH—H₂O (2 M in water, 750 uL). The mixture was stirred at        25° C. for 2 hours. On the completion, the reaction mixture was        concentrated under reduced pressure to get a crude compound (146        mg, crude) as a white solid.    -   Step 8:        (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.        To a solution of        (R)-6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylic        acid (146.46 mg, 252 umol) in DMSO (2 mL) was added DIEA (98.0        mg, 758 umol),        (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide        (120 mg, 278 umol), EDCI (58.1 mg, 303 umol) and HOAt (41.3 mg,        303 umol). The mixture was stirred at 25° C. for 12 hours. On        completion, the reaction mixture was filtered by disposable        needle filter. The residue was purified by prep-HPLC (column:        Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.05%        HCl)-MeOH]; B %: 35%-65%, 10 min) to get the title compound        (51.8 mg, 49.6 umol, 19.6% yield, 98.6% purity, HCl) as a yellow        solid. ¹H NMR (400 MHz, DMSO-d₆) δ =14.13-13.76 (m, 1H),        11.36-11.15 (m, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.64-8.57 (m,        1H), 8.38 (d, J=5.2 Hz, 1H), 7.77-7.62 (m, 2H), 7.41 (d, J=6.0        Hz, 5H), 7.24-7.21 (m, 1H), 7.08-7.03 (m, 1H), 6.71-6.61 (m,        1H), 6.29-6.14 (m, 1H), 4.54-4.50 (m, 1H), 4.45-4.39 (m, 2H),        4.37-4.33 (m, 1H), 4.25-4.19 (m, 1H), 3.70-3.61 (m, 2H),        3.52-3.32 (m, 4H), 3.19-3.11 (m, 3H), 2.88-2.75 (m, 3H),        2.47-2.43 (m, 4H), 2.42-2.27 (m, 3H), 1.98 (s, 11H), 1.93-1.86        (m, 1H), 1.54 (d, J=6.4 Hz, 3H), 0.94-0.89 (m, 9H). LC-MS (ESI,        m/z): [M/2+1]=496.9.

Example 2.(2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((S)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-4-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(I-14)

I-14 was prepare by methods substantially similar to the steps describedabove to prepare I-13. ¹H NMR (400 MHz, DMSO-d₆) δ =14.04-13.88 (m, 1H),11.39-11.10 (m, 1H), 9.15 (s, 1H), 8.77-8.68 (m, 1H), 8.61 (t, J=5.6 Hz,1H), 8.38 (d, J=5.2 Hz, 1H), 7.79-7.57 (m, 2H), 7.48-7.38 (m, 5H),7.28-7.20 (m, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.67 (d, J=5.2 Hz, 1H),6.33-6.07 (m, 1H), 5.17-5.08 (m, 1H), 4.56-4.50 (m, 3H), 4.46-4.39 (m,3H), 4.35 (s, 1H), 4.22 (dd, J=5.2, 16.0 Hz, 1H), 3.70-3.60 (m, 2H),3.54-3.30 (m, 4H), 3.20-3.13 (m, 3H), 2.90-2.73 (m, 3H), 2.46 (s, 3H),2.41-2.32 (m, 2H), 2.23-2.13 (m, 4H), 2.12-2.00 (m, 5H), 1.89 (ddd,J=4.4, 8.4, 12.8 Hz, 1H), 1.55 (d, J=6.4 Hz, 3H), 0.94-0.89 (m, 9H).LC-MS (ESI, m/z): [M+1]⁺=992.7.

Example 3.(2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(I-38)

-   -   Step 1:        3-(2-(methoxymethoxy)phenyl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,        5]pyrrolo[2,3-c]pyridazine. A mixture of        [2-(methoxymethoxy)phenyl]boronic acid (2.45 g, 13.5 mmol),        12-chloro-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene        (2 g, 8.98 mmol), BrettPhos Pd G3 (814 mg, 898 umol) and K₂CO₃        (3.72 g, 27.0 mmol) in dioxane (30 mL) and H₂O (6 mL) was        degassed and purged with N₂ for 3 times, and then the mixture        was stirred at 80° C. for 12 hours under N₂ atmosphere. The        reaction mixture was partitioned between ethyl acetate (300 mL)        and water (200 mL). The organic phase was separated, washed with        brine (100 mL*2) and dried over Na₂SO₄, filtered and        concentrated under reduced pressure to give a residue. The crude        product was purified by reversed-phase HPLC (0.1% NH₃·H₂O) to        give the title compound (1.5 g, 51% yield) as a yellow solid. ¹H        NMR (400 MHz, DMSO-d₆) δ =12.25-11.85 (m, 1H), 7.96 (s, 1H),        7.71 (dd, J=1.6, 7.6 Hz, 1H), 7.42-7.35 (m, 1H), 7.23 (d, J=7.6        Hz, 1H), 7.14 (dt, J=1.2, 7.6 Hz, 1H), 5.20 (q, J=6.4 Hz, 2H),        4.06 (q, J=6.4 Hz, 1H), 3.30 (s, 3H), 3.23-3.18 (m, 1H), 2.90        (ddd, J=4.8, 8.4, 12.4 Hz, 1H), 2.84-2.75 (m, 1H), 2.72-2.65 (m,        1H), 1.39 (d, J=6.4 Hz, 3H). LC/MS (ESI, m/z): [M+1]⁺=325.0.    -   Step 2:        6-(5-bromopyrimidin-2-yl)-3-(2-(methoxymethoxy)phenyl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazine.        To a solution of        12-[2-(methoxymethoxy)phenyl]-3-methyl-4,8,10,11-tetrazatricyclo        [7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene (800 mg, 2.47 mmol)        and 5-bromo-2-chloro-pyrimidine (429 mg, 2.22 mmol) in DMSO (8        mL) was added DIEA (956 mg, 7.40 mmol). The mixture was stirred        at 110° C. for 2 hours. The reaction mixture was partitioned        between ethyl acetate (80 mL) and water (70 mL). The organic        phase was separated, washed with brine (35 mL*2) and dried over        Na₂SO₄, filtered and concentrated under reduced pressure to give        a residue. The residue was purified by column chromatography        (SiO₂, Petroleum ether/Ethyl acetate=2/1 to 0/1) to give the        title compound (1 g, 77% yield, 92% purity) as a yellow solid.        LC/MS (ESI, m/z): [M+1]⁺=481.2.    -   Step 3: tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate.        A mixture of        4-(5-bromopyrimidin-2-yl)-12-[2-(methoxymethoxy)phenyl]-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene        (1 g, 2.08 mmol), tert-butyl        4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate        (642 mg, 2.08 mmol), K₂CO₃ (861 mg, 6.23 mmol) and        Pd(dppf)Cl₂·CH₂Cl₂ (170 mg, 208 umol) in dioxane (15 mL) and H₂O        (3 mL) was degassed and purged with N₂ for 3 times, and then the        mixture was stirred at 80° C. for 12 hours under N₂ atmosphere.        The reaction mixture was partitioned between ethyl acetate (100        mL) and water (100 mL). The organic phase was separated, washed        with brine (50 mL*2) and dried over Na₂SO₄, filtered and        concentrated under reduced pressure to give a residue. The        residue was purified by column chromatography (SiO₂, Petroleum        ether/Ethyl acetate=10/1 to 0/1) to give the title compound (900        mg, 67% yield, 90% purity) as a yellow solid. ¹H NMR (400 MHz,        DMSO-d₆) δ =12.20 (s, 1H), 8.52 (s, 2H), 8.06 (s, 1H), 7.71 (d,        J=7.6 Hz, 1H), 7.44-7.37 (m, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.15        (t, J=7.6 Hz, 1H), 6.08 (s, 1H), 5.94 (q, J=6.4 Hz, 1H),        5.26-5.17 (m, 2H), 5.09 (dd, J=4.8, 13.2 Hz, 1H), 3.97 (s, 2H),        3.52 (t, J=5.2 Hz, 2H), 3.45-3.36 (m, 1H), 3.31 (s, 3H),        3.00-2.86 (m, 2H), 2.42 (s, 2H), 1.49 (d, J=6.4 Hz, 3H), 1.41        (s, 9H). LC/MS (ESI, m/z): [M+1]⁺=584.5.    -   Step 4: tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidine-1-carboxylate.        To a solution of tert-butyl        4-[2-[12-[2-(methoxymethoxy)phenyl]-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate        (1 g, 1.71 mmol) in THF (15 mL) was added Pd/C (10%, 2 g),        Pd(OH)₂/C (20%, 2 g) under N₂ atmosphere. The suspension was        degassed and purged with H₂ for three times. The mixture was        stirred under H₂ (15 Psi) at 25° C. for 12 hours. The reaction        mixture was filtered and concentrated under reduced pressure to        give the crude compound (560 mg, crude) as a yellow solid. LC/MS        (ESI, m/z): [M+1]⁺=586.5.    -   Step 5: (R)-tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidine-1-carboxylate        acid and (S)-tert-butyl        4-(2-(3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,        5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidine-1-carboxylate.        Tert-butyl        4-[2-[12-[2-(methoxymethoxy)phenyl]-3-methyl-4,8,10,11-tetrazatricyclo        [7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]piperidine-1-carboxylate        (560 mg, 956 umol) was separated by SFC (column: DAICEL        CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O,        MeOH]; B %: 60%-60%, 6.5; 80 min) to give 5-P1 (260 mg, 444        umol, 46% yield) as a white solid. LC/MS (ESI, m/z):        [M+1]⁺=586.6; 5-P2 (260 mg, 444 umol, 46% yield) as a white        solid. LC/MS (ESI, m/z): [M+1]⁺=586.6.    -   Step 6:        (R)-2-(5-methyl-6-(5-(piperidin-4-yl)pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol.        To a solution of tert-butyl        4-[2-[(3R)-12-[2-(methoxymethoxy)phenyl]-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]piperidine-1-carboxylate        (260 mg, 444 umol) in TFA (0.5 mL) and DCM (2.5 mL). The mixture        was stirred at 25° C. for 12 hours. The reaction mixture was        filtered and concentrated under reduced pressure to give the        crude compound (196 mg, crude) as a yellow solid. LC/MS (ESI,        m/z): [M+1]=442.3.    -   Step 7: (R)-methyl        6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,        4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylate.        To a solution of        2-[(3R)-3-methyl-4-[5-(4-piperidyl)pyrimidin-2-yl]-4,8,10,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraen-12-yl]phenol        (146 mg, 331 umol) and methyl        2-oxospiro[3.3]heptane-6-carboxylate (66.7 mg, 397 umol) in THF        (1 mL) was added KOAc (32.5 mg, 331 umol), AcOH (59.6 mg, 992        umol) and NaBH(OAc)₃ (175 mg, 827 umol). The mixture was stirred        at 0-25° C. for 12 hours. The reaction mixture was quenched by        addition water (1 mL) and then filtered and concentrated under        reduced pressure to give a residue. The crude product was        purified by reversed-phase HPLC (0.1% FA condition) to give the        title compound (170 mg, 85% yield, 98% purity) as a yellow        solid. LC/MS (ESI, m/z): [M+1]⁺=594.2.    -   Step 8:        (R)-6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylic        acid. To a solution of methyl        2-[4-[2-[(3R)-12-(2-hydroxyphenyl)-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.0^(2,7)]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-1-piperidyl]spiro        [3.3]heptane-6-carboxylate (220 mg, 371 umol) in THF (1 mL) was        added LiOH—H₂O (2 M in water, 1 mL). The mixture was stirred at        25° C. for 1 hour. The reaction mixture was filtered and        concentrated under reduced pressure to give the crude compound        (215 mg, crude) as a yellow oil. LC/MS (ESI, m/z): [M+1]⁺=580.1.    -   Step 9:        (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)        spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)        pyrrolidine-2-carboxamide. To a solution of        2-[4-[2-[(3R)-12-(2-hydroxyphenyl)-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-1-piperidyl]spiro[3.3]heptane-6-carboxylic        acid (165 mg, 285 umol) and        (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide        (110 mg, 256 umol) in DMSO (1 mL) was added EDCI (81.9 mg, 427        umol), HOAt (58.1 mg, 427 umol, 59.7 uL) and DIEA (110 mg, 854        umol, 149 uL). The mixture was stirred at 25° C. for 12 hours.        The reaction mixture was purified by prep-HPLC (column: Welch        Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05%        HCl)-ACN]; B %: 18%-48%, 11 min) to give the title compound (100        mg, 33% yield, 98% purity, HCl salt) as a yellow solid. ¹H NMR        (400 MHz, DMSO-d₆) δ =14.09-13.98 (m, 1H), 11.33 (d, J=8.0 Hz,        1H), 9.30 (s, 1H), 8.70 (s, 1H), 8.64 (t, J=6.0 Hz, 1H), 8.38        (s, 2H), 7.72 (dd, J=3.6, 9.2 Hz, 1H), 7.63 (dd, J=1.2, 7.6 Hz,        1H), 7.46-7.39 (m, 5H), 7.25 (d, J=8.0 Hz, 1H), 7.05 (t, J=7.6        Hz, 1H), 6.13 (q, J=6.4 Hz, 1H), 5.07 (d, J=13.2 Hz, 1H), 4.51        (d, J=9.2 Hz, 1H), 4.45-4.38 (m, 2H), 4.34 (s, 1H), 4.22 (dd,        J=4.8, 16.0 Hz, 1H), 3.69-3.59 (m, 2H), 3.56-3.43 (m, 2H),        3.39-3.26 (m, 2H), 3.20-3.10 (m, 3H), 2.87-2.72 (m, 3H),        2.48-2.42 (m, 4H), 2.39-2.29 (m, 2H), 2.22-2.01 (m, 8H),        2.00-1.83 (m, 4H), 1.54 (d, J=6.4 Hz, 3H), 0.91 (s, 9H). LC/MS        (ESI, m/z): [M+1]⁺=992.8.    -   Step 10:        (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)        spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)        pyrrolidine-2-carboxamide and        (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((R)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)        piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.        (2S,4R)-4-hydroxy-1-[(2S)-2-[[2-[4-[2-[(3R)-12-(2-hydroxyphenyl)-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-1-piperidyl]spiro[3.3]heptane-6-carbonyl]amino]-3,3-dimethyl-butanoyl]-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide        (116 mg, 117 umol) was separated by SFC (column: DAICEL        CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O,        MeOH]; B %: 65%-%, 10; 200 min) to afford two compounds (I-40        and I-41). Peak 1 was purified by prep-HPLC (column: Welch        Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.05%        HCl)-ACN]; B %: 13%-43%, 10 min) to give the title compound        (28.8 mg, 23% yield, 98% purity, HCl salt) as a yellow solid. ¹H        NMR (400 MHz, DMSO-d₆) δ =13.92 (s, 1H), 11.23 (d, J=7.2 Hz,        1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 8.36        (s, 2H), 7.72 (d, J=9.2 Hz, 1H), 7.63 (dd, J=1.6, 7.6 Hz, 1H),        7.50-7.36 (m, 5H), 7.23 (d, J=8.4 Hz, 1H), 7.06 (t, J=7.6 Hz,        1H), 6.13 (q, J=6.4 Hz, 1H), 5.08 (d, J=13.2 Hz, 1H), 4.52 (s,        1H), 4.50 (s, 1H), 4.45-4.39 (m, 4H), 4.35 (s, 1H), 4.22 (dd,        J=5.2, 16.0 Hz, 1H), 3.71-3.59 (m, 2H), 3.53-3.42 (m, 2H),        3.42-3.27 (m, 2H), 3.23-3.08 (m, 3H), 2.82-2.73 (m, 2H), 2.45        (s, 3H), 2.34 (t, J=10.0 Hz, 2H), 2.26-2.17 (m, 2H), 2.14-2.01        (m, 6H), 1.99-1.85 (m, 3H), 1.54 (d, J=6.4 Hz, 3H), 0.95-0.88        (m, 9H). LC/MS (ESI, m/z): [M+1]⁺=992.8. Peak 2 was purified by        prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile        phase: [water (0.05% HCl)-ACN]; B %: 14%-44%, 10 min) to give        the title compound (28.0 mg, 23% yield, 99% purity, HCl salt) as        a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ =13.79 (s, 1H), 11.04        (d, J=7.2 Hz, 1H), 9.04 (s, 1H), 8.76-8.70 (m, 1H), 8.59 (t,        J=6.0 Hz, 1H), 8.36 (s, 2H), 7.75 (d, J=9.2 Hz, 1H), 7.66 (dd,        J=1.6, 7.6 Hz, 1H), 7.50-7.36 (m, 5H), 7.19 (d, J=8.0 Hz, 1H),        7.11-7.04 (m, 1H), 6.13 (q, J=6.8 Hz, 1H), 5.15-5.05 (m, 1H),        4.53 (d, J=9.2 Hz, 1H), 4.47-4.39 (m, 2H), 4.36 (s, 1H), 4.22        (dd, J=5.2, 16.0 Hz, 1H), 3.71-3.61 (m, 3H), 3.52-3.42 (m, 2H),        3.36 (t, J=13.2 Hz, 2H), 3.22-3.10 (m, 3H), 2.81-2.71 (m, 2H),        2.45 (s, 3H), 2.43-2.31 (m, 3H), 2.25-1.85 (m, 12H), 1.55 (d,        J=6.4 Hz, 3H), 0.96-0.90 (m, 9H). LC/MS (ESI, m/z):        [M+1]⁺=992.8.

Example 4.(2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((S)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(I-37)

-   -   Step 1: (S)-methyl        6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylate.        To a solution of        2-[(3S)-3-methyl-4-[5-(4-piperidyl)pyrimidin-2-yl]-4,8,10,11-tetrazatricyclo[7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-12-yl]phenol        (0.2 g, 453 umol) and methyl        2-oxospiro[3.3]heptane-6-carboxylate (91.4 mg, 544 umol) in DMSO        (5 mL) was added KOAc (111 mg, 1.13 mmol), HOAc (68 mg, 1.13        mmol), NaBH(OAc)₃ (288 mg, 1.36 mmol) and 4A MS (0.3 g, 453        umol). The mixture was stirred at 25° C. for 12 hours. The        reaction mixture was concentrated under reduced to give a crude        product. The crude product was purified by prep-TLC (SiO₂, DCM:        MeOH=10:1) to give the title compound (220 mg, 81.8% yield, 97%        purity) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=594.5.    -   Step 2:        (S)-6-(4-(2-(3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxylic        acid. To a solution of methyl        2-[4-[2-[(3S)-12-(2-hydroxyphenyl)-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-1-piperidyl]spiro[3.3]heptane-6-carboxylate        (0.22 g, 371 umol) in THF (3 mL) was added LiOH—H₂O (2 M, 1.10        mL). The mixture was stirred at 25° C. for 1 hour. The reaction        mixture was concentrated under reduced pressure to give a crude        product. The crude product was purified by reversed-phase Flash        (0.1% FA condition) to give title compound (0.048 g, 68.4%        yield, 98% purity) as a white solid. LC/MS (ESI, m/z):        [M+1]⁺=580.2.    -   Step 3:        (2S,4R)-4-hydroxy-1-((S)-2-(6-(4-(2-((S)-3-(2-hydroxyphenyl)-5-methyl-7,8-dihydro-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-c]pyridazin-6(9H)-yl)pyrimidin-5-yl)piperidin-1-yl)spiro[3.3]heptane-2-carboxamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.        To a solution of        2-[4-[2-[(3S)-12-(2-hydroxyphenyl)-3-methyl-4,8,10,11-tetrazatricyclo[7.4.0.0²,7]trideca-1(9),2(7),10,12-tetraen-4-yl]pyrimidin-5-yl]-1-piperidyl]spiro[3.3]heptane-6-carboxylic        acid (150.00 mg, 258.76 umol, 1 eq) and        (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide        (111 mg, 259 umol) in DMSO (3 mL) was added EDCI (59.5 mg, 311        umol), HOAt (42.3 mg, 311 umol) and DIEA 167 mg, 1.29 mmol). The        mixture was stirred at 25° C. for 12 hours. The mixture was        filtered to give a crude product. The crude product was purified        by prep-HPLC(column: Welch Xtimate C18 150*25 mm*5 u S; mobile        phase: [water (0.05 HCl)-ACN]; B: 11%-41%, 11 min) to give title        compound (18.7 mg, 6.91% yield, 950 purity) as a white solid. ¹H        NMR (400 MHz, DMSO-d6) δ ppm: 8.99 (s, 11H), 8.73 (s, 11H), 8.56        (t, J=5.6 Hz, 11H), 8.35 (s, 2H), 7.78-7.70 (m, 2H), 7.40 (d,        J=6.4 Hz, 5H), 7.14-7.04 (in, 2H), 6.11 (d, J=6.0 Hz, 1H), 5.09        (dd, J=3.2 Hz, J=10.4 Hz, 1H), 4.53 (d, J=9.6 Hz, 1H), 4.46-4.39        (m, 2H), 4.37-4.33 (in, 1H), 4.25-4.18 (in, 1H), 3.20-3.04 (m,        4H), 2.85-2.63 (m, 4H), 2.46-2.44 (m, 4H), 2.33 (d, J=1.6 Hz,        4H), 2.30-1.84 (m, 15H), 1.54 (d, =6.4 Hz, 3H), 1.26-1.13 (m,        1H), 0.94-0.89 (i, 9H); LC/MS (ESI, m/z): [M+1]⁺=992.3.

Example 5. MSD SMARCA2 Degradation in NCI-H299 Cell Line

Cell Line Vendor Medium NCI-H1299 ATCC RPMI MEDIUM 1640 + 10% FBS + 1xPS

Regents Vendor Cat# RPMI MEDIUM 1640 Invitrogen A10491-01 Fetal bovineserum (FBS) Hyclone SH30406.05 Penicillin-Streptomycin (100×) SolarBioP1400 Phosphate Buffered Saline Solarbio P1020-500 (PBS) RIPA Bufferwith EDTA BBP 115D cOmplete ULTRA Tablets, Roche Applied 05892791001Mini, EDTA-free, EASYpack Science MSD Standard Plate Meso ScaleDiscovery L15XA-3 Anti-SMARCA2/BRM antibody Abcam ab223735 SULFO-TAGanti-rabbit Meso Scale Discovery R32AB-5 antibody MSD Blocker A MesoScale Discovery R93BA-4 MSD Read Buffer T (4×) Meso Scale DiscoveryR92TC-1 Tris Buffered Saline with CST 9997S Tween ® 20 (TBST-10×)

Instrument Vendor Cat# Cell counter Invitrogen Countess CentrifugeEppendorf 5810R CO₂ Incubator Thermo Model: 371 Vortex IKA MS3 digitalEcho Liquid Handler Labcyte 550 TECAN TECAN Freedom EVO200 PERSONALPIPETTOR Apricot Designs PP5 + 1 MSD reader Meso Scale Discovery MSDSECTOR 6000 96 well plate Corning 3599 225 cm² Cell Culture Corning431081 Flask 50 mL centrifuge tube BD-Falcon 352098 15 mL centrifugetube BD-Falcon 352097

Cell Culture: Cells are cultured in exponential growth phase.

Compound Preparation and Treatment: NCI-H1299 cells are seeded into the96-well plate at 4.0*10⁴ cells per 100 ul per well. Incubate the platein the incubator overnight. The next day, compounds are diluted todesigned stock concentration by TECAN, then perform a 3 fold, 9-pointdilution via transferring 15 μL compound into 30 μL DMSO using Apricot.200 nL diluted compound from compound source plate are transferred intothe 96-intermediate plate as designated by using Echo550, followed with100 μl culture medium to make the 2× compound solution. Cell plate arechanged with 80 μl of fresh culture medium and 80 μl of 2× compoundsolution is added into the well to achieve the final designedconcentration. Cell plate is then shaken at 720 rpm for 5 min andincubated for 24 hours in the incubator.

Sample Preparation: Media was aspirated from the cultures and the plateis washed with PBS twice. 60 μL of pre-chilled PIPA lysis buffer (BostonBioProducts BP-115D) with protease inhibitor are directly added into thewell to lyze the cells for 20 minutes at 4° C. Cell lysates werecollected.

MSD Procedure: The MSD plate is coated with 40 l cell lysate andincubated at 4° C. overnight. The next day, the MSD coated bare plate iswashed 3 times with 150 μl 1× TBST per well, blocked with 150 μl ofblocking buffer per well, and shaken for 1 hour at RT, 600 rpm. Blockingbuffer is 3% Blocker A in TBST. MSD plate is then washed 3 times with150 μl 1× TBST per well and Primary Detection antibody (Rabbitanti-SMARCA2/BRM antibody, 100 μg/ml, ab223735) is added to a final[conc.]: 0.3 μg/ml, 25 ul/well and shaken for 1 hour at RT, 600 rpm.Antibody is prepared in Antibody Detection buffer (1% Blocker A in 1×TBST). The MSD plate is then washed 3 times with 150 μl 1× TBST perwell. Secondary Detection antibody (SULFO-TAG anti-species antibody) isthen added to a final [conc.]: 1 μg/ml, 25 l/well, and shaken for 1 hourat RT, 600 rpm. Antibodies are prepared in Antibody Detection buffer (1%Blocker A in 1× TBST). MSD plate is washed 3 times with 150 μl 1× TBSTper well and 2× MSD reading buffer is added, 150 W per well, and dilutedfrom 4× with water. MSD instrument is then read.

Data Analysis: The percentage of relative level of SMARCA2 level iscalculated following equation below.

${\%{Relative}{Level}} = {100\% \times \frac{{{MSD}{Signal}_{Sample}} - {{MSD}{Signal}_{LC}}}{{MSDSingal}_{HC} - {{MSD}{Signal}_{LC}}}}$

LC: A2780, SMARCA2 negative cells. HC: NCI-H1299 cells treated withDMSO.

SMARCA2 protein degradation in H1299 cells for compounds of theinvention are presented in Table 3. The letter codes for SMARCA2degradation potency (DC₅₀) include: A (<100 nM), B (100-500 nM), C(501-1000 nM), and D (>1000 nM). The letter codes for the percentage ofSMARCA2 degradation after 24 hours (Dmax %) include: A (>90%degradation), B (>70-90% degradation), C (50-70% degradation), and D(<50% degradation).

TABLE 3 SMARCA2 MSD H1299 Degradation Results. I-# SMARCA2 MSD SMARCA2MSD H1299 degradation H1299 degradation 24 h: Average 24 h: Averageexternal-Abs IC50 Dmax % (nM)

Example 6. MSD SMARCA2 Degradation in A549 Cell Line

Cells were seeded into 96-well plates (A549 cells: 2×104 cells/well/100ul media) and incubated overnight. The next day, 200 nL compound wereadded into the intermediate plate with Echo (Labcyte 550) from sourceplate containing a 3-fold serial dilution from top concentration of 1mM. The culture medium was changed with 80 ul of fresh medium and 80 uLof 2× compound solution was added into the well to make a finalconcentration of 1000 nM, 333.3 nM, 111.1 nM, 37.04 nM, 12.35 nM, 4.115nM, 1.372 nM, 0.457 nM, 0.152 nM and 0 nM (DMSO). The wells were mixedand then incubated for 24 hours. The media was aspirated from thecultures and 60 ul pre-chilled PIPA lysis buffer (Boston BioProductsBP-115D) with protease/phosphatase inhibitor (Roche 05892791001/Roche04906837001) was added into the well to lyze the cells for 20 minutes at4° C. The MSD plate (L15XA) was coated with 40 uL cell lysate andincubated at 4° C. overnight. The next day, the plate was washed threetimes with TBST (CST #9997S), 150 ul/well. The MSD plates was blockedwith 150 ul blocking buffer per well and shaked for 1 hr at RT, 600 rpm.The blocking buffer was 3% Blocker A (MSD, R93BA-4) in TBST. The MSDplate was washed three times with 150 uL/well of TBST and 25 ul/well ofdetection antibody (Rabbit anti-SMARCA2/BRM antibody, 100 μg/mL,ab223735) was added at final concentration of 1 ug/mL diluted in 1%Blocking buffer and shaken for 1 hour at RT, 600 rpm. The MSD plate waswashed three times with 150 ul/well of TBST and 25 ul/well of SULFO-TAGanti-rabbit antibody (MSD, R32AB-1) was added at final concentration of1 ug/ml diluted in 1% Blocking buffer and shaken for 1 hour at RT, 600rpm. The MSD plate was washed three times with 150 uL/well of TBST and150 ul/well of 2× MSD reading buffer diluted from 4× (MSD, R92TC-2) withwater was added. Lastly, the MSD instrument was read.

SMARCA2 protein degradation in A549 cells for compounds of the inventionare presented in Table 4. The letter codes for SMARCA2 degradationpotency (DC₅₀) include: A (<100 nM), B (100-500 nM), C (501-1000 nM),and D (>1000 nM). The letter codes for the percentage of SMARCAdegradation after 24 hours (Dmax %) include: A (>90% degradation), B(>70-90% degradation), C (50-70% degradation), and D (<50% degradation).

TABLE 4 SMARCA2 MSD A549 SMARCA2 degradation MSD A549 24 h: Averagedegradation external-Abs 24 h: Average I-# DC₅₀ (nM) Dmax % I-13 D DI-14 B B I-37 B B I-38 A A I-40 B B I-41 B B

Example 7. SMARCA2 and SMARCA4 Western Blot MV4-11 Degradation

Cells were seeded into 6-well plates (MV4-11: 4×106 cells/well/1 ml) and1 ml of 2×compound solution was added into the well to make the finalconcentration and the plates were mixed well and incubated for 24 hours(No cytotoxicity was observed). The cell were collected with media andspun at 3000 rpm for 5 minutes. The supernatant was aspirated and thewell and the cells were washed with cold PBS once and combined forcentrifugation again; the supernatant aspirated again. 200 uLpre-chilled RIPA lysis buffer (Boston BioProducts BP-115D) withprotease/phosphatase inhibitor (Roche 05892791001/Roche 04906837001) wasdirectly added into the tube to lyze the cells for 20 minutes on ice.The cell lysate were collected into EP tubes and spun at 13000 rpm for20 minutes and 72 uL supernatant was transferred to a fresh EP tubecontaining 18 uL of 5× loading buffer (Beyotime Bio P0015) to make theloading samples. The samples were heated to 100° C. for 10 minutes andcooled to RT and microcentrifuged. 20 uL of samples were loaded ontoSDS-PAGE gel (Novex, WG1402BOX) and the gel was run at 80 V for 20minutes and 120 V for 1.5 hours. The samples were electrotransfer to aNC membrane using wet-transfer method with 250 mA for 2.5 hours. Themembrane was blocked with LICOR blocking buffer (LI COR,927-50000) for 1hour. The membrane was washed three times with TBST(CST #9997S), 5minutes each. Incubation was performed with primary antibody prepared inblocking buffer with 0.1% Tween-20 (Solarbio, P8220) at 4° C. overnight(Anti-SMARCA2/BRM antibody (ab15597) 1:500; Anti-BRG1 antibody [EPR3912](ab108318) 1:1000; Rabbit anti-Baf180 antibody [EPR15860](Abcam,ab196022) 1:1000; mouse anti-beta-Actin (8H10D10) (CST #3700)1:10000). The membrane was washed three times with TBST, 5 minutes each.Incubation with secondary antibody was performed for 1 hour at RT(anti-rabbit IgG (Licor,926-32211) 1:5000; anti-mouse IgG (LI-COR,926-68070) 1:5000). The membrane was washed three times with 5 minuteseach and lastly the LiCOR was read.

SMARCA2/SMARCA4 protein degradation selectivity in MV4-11 cells forcompounds of the invention are presented in Table 5. The letter codesfor SMARCA2/4 degradation potency (DC₅₀) include: A (<100 nM), B(100-500 nM), C (501-1000 nM), and D (>1000 nM). The letter codes forthe percentage of SMARCA degradation after 24 hours (Dmax %) include: A(>90% degradation), B (>70-90% degradation), C (50-70% degradation), andD (<50% degradation).

TABLE 5 SMARCA2 MSD A549 Degradation and SMARCA2/4 MV4-11 SelectivityResults. SMARCA2 SMARCA4 MSD MV411 SMARCA2 MSD MV411 SMARCA4 degradationMSD MV411 degradation MSD MV411 24 h: Mean degradation 24 h: Meandegradation external-Abs 24 h: average external-Abs 24 h: average I-#DC50 (nM) Dmax % DC50 (nM) Dmax % I-13 C C D C I-14 A B D C I-37 B C — —I-38 A B D D I-40 A B D D I-41 A B D D

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-26. (canceled)
 27. A method of degrading one or more of SMARCA2,SMARCA4, and PB1 protein in a patient or biological sample comprisingadministering to said patient, or contacting said biological sample witha compound of formula I-a-3:

or a pharmaceutical composition thereof, wherein: Ring W is

Ring Y is a fused-ring selected from 6-membered aryl, 5 to 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 4 to 9-membered saturated orpartially unsaturated monocyclic, bicyclic, or bridged bicycliccarbocyclyl or heterocyclyl with 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur: each of R^(x) andR^(y) is independently hydrogen, R halogen, —CN, —NO₂, —OR—SR, —NR₂,—SiR₃, —S(O)₂R—S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R,—OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂,—N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; ortwo R^(x) groups or two R^(y) groups are optionally taken together toform an optionally substituted 5-7 membered partially unsaturated oraryl fused ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or: two R groups on the sameatom are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the atom to which they are attached,independently selected from nitrogen, oxygen, and sulfur; each R^(z) isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; x is 0, 1, 2, 3, 4, or 5; y is 0, 1, 2, 4, or 5; L¹ is acovalent bond or a bivalent, saturated or unsaturated, straight orbranched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methylene units of L areindependently replaced by —Cy—, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—,—Si(OH)₂—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—,—C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—,—C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—,

each —Cy— is independently an optionally substituted bivalent ringselected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 5-11membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 5-11 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and an 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10; and DIM is a degradation inducing moiety selected from a ligasebinding moiety (LBM), wherein the LBM is a cereblon E3 ligase bindingmoiety of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

X² is a carbon atom or silicon atom; X³ is a bivalent moiety selectedfrom —CR₂—, —NR—, —O—, —S—, and —Si(R₂)—; R1 is hydrogen, halogen, —CN,—OR, —SR, —S(O)R, —S(O)R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,—Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄aliphatic; each R² is independently hydrogen, R, halogen, —CN, —NO₂,—OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,—C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,—OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)(NR₂),—OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, —N(R)S(O)₂R,—NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂), —N(R)P(O)(NR₂)₂, or—N(R)S(O)₂R; Ring A is a bicyclic or tricyclic ring selected from

Ring B is a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, and a 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen and sulfur; R³ is selected from hydrogen, halogen, —OR, —N(R)₂,and —SR; each R⁴ is independently hydrogen, R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R; R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN; each R⁶ isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; L¹ is a covalent bond or a C₁₋₃ bivalent straight or branchedsaturated or unsaturated hydrocarbon chain wherein 1-2 methylene unitsof the chain are independently and optionally replaced with —O—, —C(O)—,—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂— or —(C)═CH—; andm is 0, 1, 2, 3 or
 4. 28. A method of treating one or moreSMARCA2-mediated, SMARCA4-mediated, or PB1-mediated disorder, disease,or condition in a patient comprising administering to said patient acompound of formula I-a-3:

or a pharmaceutical composition thereof, wherein: Ring W is

Ring Y is a fused-ring selected from 6-membered aryl, 5 to 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 4 to 9-membered saturated orpartially unsaturated monocyclic, bicyclic, or bridged bicycliccarbocyclyl or heterocyclyl with 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur; each of R^(x) andR^(y) is independently hydrogen, R halogen, —CN, —NO₂, —OR, —SR, —NR₂,—SiR₃, —S(O)₂R—S(O)₂NR₂, —S(O)R, —CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR,—C(O)NR₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R,—OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂, —OP(O)(OR)NR₂, —OP(O)(NR₂)₂—,—N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —NP(O)R₂,—N(R)P(O)(OR)₂, —N(R)P(O)(OR)NR₂, —N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; ortwo R^(x) groups or two R^(y) groups are optionally taken together toform an optionally substituted 5-7 membered partially unsaturated oraryl fused ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or: two R groups on the sameatom are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the atom to which they are attached,independently selected from nitrogen, oxygen, and sulfur; each R^(z) isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; x is 0, 1, 2, 3, 4, or 5; y is 0, 1, 2, 4, or 5; L is a covalentbond or a bivalent, saturated or unsaturated, straight or branched C₁₋₅₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by —Cy—, —O—, —N(R)—, —Si(R)₂—, —Si(OH)(R)—, —Si(OH)₂—,—P(O)(OR)—, —P(O)(R)—, —P(O)(NR₂)—, —S—, —OC(O)—, —C(O)O—, —C(O)—,—S(O)—, —S(O)₂—, —N(R)S(O)₂—, —S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)C(O)O—,

each —Cy— is independently an optionally substituted bivalent ringselected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 5-11membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 5-11 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and an 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10; and DIM is a degradation inducing moiety selected from a ligasebinding moiety (LBM), wherein the LBM is a cereblon E3 ligase bindingmoiety of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is a bivalentmoiety selected from a covalent bond, —CH₂—, —CHCF₃—, —SO₂—, —S(O)—,—P(O)R—, —P(O)OR—, —P(O)NR₂—, —C(O)—, —C(S)—, and

X² is a carbon atom or silicon atom; X³ is a bivalent moiety selectedfrom —CR₂—, —NR—, —O—, —S—, and —Si(R₂)—; R¹ is hydrogen, halogen, —CN,—OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, or an optionallysubstituted C₁₋₄ aliphatic; each R² is independently hydrogen, R⁶,halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R)₃, —S(O)₂R—S(O)₂N(R)₂,—S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,—C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —OP(O)R₂, —OP(O)(OR)₂,—OP(O)(OR)(NR₂), —OP(O)(NR₂)₂—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂,—N(R)S(O)₂R, —NP(O)R₂, —N(R)P(O)(OR)₂, —N(R)P(O)(OR)(NR₂),—N(R)P(O)(NR₂)₂, or —N(R)S(O)₂R; Ring A is a bicyclic or tricyclic ringselected from

Ring B is a fused ring selected from 6-membered aryl, 6-memberedheteroaryl containing 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partiallyunsaturated carbocyclyl, 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, and a 5-memberedheteroaryl with 1-4 heteroatoms independently selected from nitrogen,oxygen and sulfur; R³ is selected from hydrogen, halogen, —OR, —N(R)₂,and —SR; each R⁴ is independently hydrogen, R⁶, halogen, —CN, —NO₂, —OR,—SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R; R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN; each R⁶ isindependently an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; L¹ is a covalent bond or a C₁₋₃ bivalent straight or branchedsaturated or unsaturated hydrocarbon chain wherein 1-2 methylene unitsof the chain are independently and optionally replaced with —O—, —C(O)—,—C(S)—, —C(R)₂—, —CF(R)—, —C(F)₂—, —N(R)—, —S—, —S(O)₂— or —(C)═CH—; andm is 0, 1, 2, 3 or
 4. 29. The method of claim 28, further comprisingadministration of an additional therapeutic agent.
 30. The method ofclaim 28, wherein the one or more SMARCA2-mediated, SMARCA4-mediated, orPB1-mediated disorder, disease or condition is selected from a cancer, aneurodegenerative disease, a viral disease, an autoimmune disease, aninflammatory disorder, a hereditary disorder, a hormone-related disease,a metabolic disorder, a condition associated with organ transplantation,an immunodeficiency disorder, a destructive bone disorder, aproliferative disorder, an infectious disease, a condition associatedwith cell death, thrombin-induced platelet aggregation, liver disease, apathologic immune condition involving T cell activation, acardiovascular disorder, and a CNS disorder.
 31. The method of claim 30,wherein the cancer is selected from lung cancer, non-small cell lungcancer (NSCLC), small-cell lung cancer, glioma, breast cancer,pancreatic cancer, colorectal cancer, bladder cancer, endometrialcancer, penile cancer, esophagogastric cancer, hepatobiliary cancer softtissue sarcoma, ovarian cancer, head and neck cancer, renal cellcarsinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonaltumors, germ cell tumors, cervical cancer, thyroid cancer, salivarygland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma,gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocorticalcarcinoma, appendiceal cancer, small bowel cancer, non-melanoma skincancer, melanoma, leukemia, and malignant rhabdoid tumors (MRT).
 32. Themethod of claim 28, wherein the pharmaceutical composition comprises apharmaceutically acceptable carrier, adjuvant, or vehicle.
 33. Themethod of claim 28, wherein Ring Y is a fused 4 to 9-membered saturatedor partially unsaturated monocyclic, bicyclic, or bridged bicycliccarbocyclyl or heterocyclyl with 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur.
 34. The method ofclaim 28, wherein each R^(x) and R^(y) are independently hydrogen,R^(z), halogen, —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R,—CFR₂, —CF₂R, —CF₃, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, or —N(R)S(O)₂R.
 35. The method ofclaim 28, wherein X¹ is a bivalent moiety selected from —CH₂— or —C(O)—.36. The method of claim 28, wherein X² is a carbon atom.
 37. The methodof claim 28, wherein X³ is a bivalent moiety selected from —CR₂—. 38.The method of claim 28, wherein R¹ is hydrogen or C₁₋₄ aliphatic. 39.The method of claim 28, wherein each R² is independently hydrogen, R,halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R,—C(O)R, —C(O)OR, —C(O)N(R)₂, —C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂,—OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)₂, or—N(R)S(O)₂R.
 40. The method of claim 28, wherein Ring A is a bicyclicring selected from


41. The method of claim 28, wherein Ring B is a fused ring selected from6-membered aryl and 6-membered heteroaryl containing 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.
 42. The methodof claim 28, wherein the LBM is a cereblon E3 ligase binding moietyselected from:


43. The method of claim 28, wherein L is a bivalent, saturated orunsaturated, straight or branched C₁₋₂₀ hydrocarbon chain, wherein 0-6methylene units of L are independently replaced by —Cy—, —O—, —N(R)—,—S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —N(R)S(O)₂—,—S(O)₂N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, or —N(R)C(O)O—. 44.The method of claim 28, wherein each —Cy— is independently selected fromphenylenyl, a 4-7 membered saturated or partially unsaturatedcarbocyclylenyl, a 5-11 membered saturated or partially unsaturatedspiro carbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 5-11 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and a 5-6 memberedheteroarylenyl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.
 45. The method of claim 28, wherein L isselected from: